Pyridyl imidazoles, their preparation and their therapeutic application

Abstract

Disclosed are compounds of formula (I), or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1, R2, A, and n are defined herein. Also disclosed are methods of preparing such compounds, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

Description

PYRIDYL IMIDAZOLES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONCROSS-REFERENCE TO RELATED APPLICATIONS[1] This application claims priority to European Application No. 23306385.8, filed August 17, 2023, the disclosure of which is incorporated by reference herein in its entirety.TECHNICAL FIELD[2] Disclosed herein are substituted pyridyl imidazole compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof.BACKGROUND[3] MRGPRX2 is a G-protein coupled receptor (GPCR) expressed on mast cells involved in inflammation pathways, including the non-histaminergic activation of mast cells. See Meixong, J., et al., Immunity, 50, 1163-1171 (2019). MRGPRX2 is a member of the X subfamily of the Mas family of GPCRs. MRGPRX2 is activated by numerous secretagogues, including neuropeptides, eosinophil granule proteins, and antimicrobial peptides. In response to MRGPRX2 activation, mast cells may undergo degranulation and release tryptase, which preferentially triggers non-histaminergic itch, as well as chymase, carboxipeptidases, histamine, serotonin, chemokines, and cytokines. See Corbiere, A., et al., Experimental Dermatology 30, 193-200 (2020). This activation can lead to type 2 inflammation, pruritis, and pain. Preclinical data demonstrates that blocking the activation of MRGPRX2 has the potential to effectively treat a range of mast-cell-mediated diseases. See, e.g., Meixong, J., et al.; Ogasawara, H. & Noguchi, M., Cells, 10, 2906 (2021); Quan, P.L., et al., Inti. J. Molecular Sciences, 22, 4421 (2021); Al Hamwi, G., et al., Pharmacology & Therapeutics, 2:38, 108529 (2022).[4] Currently used treatments for inflammatory diseases typically have one or more of the following drawbacks: limited efficacy, need for injection, or significant side effects. MRGPRX2 antagonists of the present disclosure may provide safe, oral, and efficacious treatments for diseases, disorders and conditions involving inflammation, itch, and / or pain.BRIEF SUMMARY[5] The present disclosure describes substituted pyridyl imidazole compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof. [6] One aspect of the present disclosure is a compound of formula I, wherein: A is selected from ,eachis a single or a double bond, provided two adjacent are not bothdouble bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6haloalkyl; each instance of R3is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl;R4is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R4P is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, - OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, - NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, - S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, monocyclic heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(arylene)R13, heterocyclyl, or -(heterocyclylene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3arylalkyl, heteroaryl, and C1-C3heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, - OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, or -NR9S(=O)2NR11R12; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, C3- C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclicheteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or more R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or more R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4alkyl), -OC(=O)N(C1-C4alkyl)(C1-C4alkyl), - NHC(=O)(C1-C4alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4alkyl), -NHC(=O)N(C1-C4alkyl)(C1-C4alkyl), -N(C1-C4alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4alkyl), - (CH)qC(=O)N(C1-C4alkyl)(C1-C4alkyl), and -S(=O)2(C1-C4alkyl), and wherein two R13groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a heterocyclyl ring; X1 is halogen; m is 0 or 1; n is 1 or 2; each p is independently 1, 2, or 3; and each q is independently 1, 2, or 3;wherein when, R4and R5may be taken together with the carbons connecting them to form a 5- or 6-membered heterocyclyl ring; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,. [7] One embodiment is a compound of formula I, wherein:A is selected fromR1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R2is selected from halogen, -OR11, -NR11R12, C1-C4alkyl, C1-C4heteroalkyl, and C1- C3haloalkyl; each instance of R3is independently selected from halogen, -OR11, -NR11R12, C1-C6alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R4Pis selected from halogen, -OR11, -NR11R12, C1-C4alkyl, C1-C4heteroalkyl, and C1- C3haloalkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -SR7, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O- )R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(phenylene)R13, 4- to 6- membered heterocyclyl, or -(4- to 6-membered heterocyclene)R13; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4acyl, and C1-C4sulfonyl provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13is independently selected from halogen, C1-C4alkyl, C1-C4haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4alkyl), -OC(=O)N(C1-C4alkyl)(C1-C4alkyl), - NHC(=O)(C1-C4alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4alkyl), -NHC(=O)N(C1-C4alkyl)(C1-C4alkyl), -N(C1-C4alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4alkyl)C(=O)NH2, -N(C1-C4alkyl)C(=O)NH(C1-C4alkyl), -N(C1-C4alkyl)C(=O)N(C1-C4alkyl)(C1-C4alkyl), -(CH2)qOH, -(CH2)qO(C1-C4alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4- to 6-membered heterocyclyl ring; m is 0 or 1; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [8] One embodiment is a compound of formula I, wherein: A is selected fromR1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6;R6is selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, - NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pC(=O)OR11, -(CH2)p(phenylene)R13, or –(4- to 6- membered heterocyclene)R13; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, C3- C6 cycloalkyl, 4- to 6-membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4acyl, and C1-C4sulfonyl provided R11is not C1-C4sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13is independently selected from halogen, C1-C4alkyl, C1-C4haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -OC(=O)(C1-C4 alkyl), -OC(=O)O(C1-C4 alkyl), -(CH2)qOH, and - S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4-membered heterocyclyl ring; m is 0; n is 1;each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [9] One embodiment is a compound of formula I, wherein: A is selected fromR1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro, chloro, and methyl; R4Pis selected from hydrogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, - (CH2)OR11, -(CH2)C(=O)OR11, -(CH2)(phenylene)R13, or –(4- to 6-membered heterocyclene)R13; R7and R8are independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, 4 to 6-membered heterocyclyl, and C1-C3 monocyclic heteroarylalkyl, which groups areunsubstituted or substituted with one, two, or three of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, or -C(=O)NR11R12,; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6- membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33- to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, -C(=O)OtBu, -OC(=O)Me, -OC(=O)OMe, -OC(=O)OEt, -(CH2)OH, and -S(=O)2(Me), and wherein two R13groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form:; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0010] One embodiment is a compound of formula I, wherein the compound is of formula I-Aor an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0011] One embodiment is a compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-B ,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0012] One embodiment is a compound of formula I, wherein the compound is of formula I-D, I-D, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0013] One embodiment is a compound of formula I, wherein the compound is of formula I-G1wherein: L1 is selected from -CH2- and -N(R11)-; G1is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; and j is 0, 1, or 2; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0014] One embodiment is a compound of formula I, wherein the compound is of formula I-Hor an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0015] One embodiment is a compound of formula I, wherein the compound is of any one of formulas -J1 to I-J5,wherein: z is 0, 1, or 2 where valency permits; each instance of Z1is independently selected from halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, - S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, - (CH2)p(arylene)R13, heterocyclyl, or -(heterocyclene)R13; each instance of E1is independently selected from -CH- and -N-; E2is selected from -NH-, -O-, and -S-; and E3is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0016] One embodiment is a compound of formula I, wherein the compound is of any one of formulas I-K1 to I-K8wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0017] One embodiment is a compound of formula I, wherein R1 is selected from halogen and C1-C4 alkyl;R2is selected from halogen and C1-C4alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0018] One embodiment is a compound of formula I, wherein R1 is fluoro; R2is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0019] One embodiment is a compound of formula I, wherein R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0020] One embodiment is a compound of formula I according to any one of claims 1 to 7, wherein R4P is selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0021] One embodiment is a compound of formula I, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0022] One embodiment is a compound of formula I, wherein R5 is -S(=O)2R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0023] One embodiment is a compound selected from the compounds listed in Table 1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0024] Another aspect of the present disclosure is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0025] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from an inflammatory disorder, an allergic disorder, a skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.

[0026] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic pain.

[0027] In one embodiment, the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.

[0028] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0029] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.

[0030] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic pain.

[0031] In one embodiment, the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.

[0032] Another aspect of the present disclosure is a medicament, characterized in that it comprises the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0033] Another aspect of the present disclosure is the use of a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament intended for the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder. DETAILED DESCRIPTION

[0034] It is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching oneskilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.

[0035] As used herein “H,” “-H,” or “hydrogen” refer to a hydrogen atom or radical. In some embodiments, the hydrogen is an isotope of hydrogen. In some embodiments, the hydrogen is deuterium (D), for example a methyl, Me, or CH3 group may be CD3.

[0036] As used herein, the term “alkyl” refers to a linear or branched saturated hydrocarbon group. A CX-CYalkyl group refers to an alkyl group having between X and Y carbon atoms, for example a C1-C6alkyl group refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and the like.

[0037] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom. A CX-CY haloalkyl group refers to a haloalkyl group having between X and Y carbon atoms, for example a C1-C6haloalkyl group refers to a haloalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to one or more halogen atoms). Exemplary haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1,2-difluoroethyl, 1,1,2,2-tetrafluoroethyl, and the like.

[0038] As used herein, the term “halogen” refers to fluoro, chloro, bromo, or iodo.

[0039] As used herein, the term “heteroalkyl” refers to a linear or branched, non-cyclic saturated group containing 1, 2, or 3 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different. Heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylthio, and alkylthioalkyl groups. A CX- CYheteroalkyl group refers to a heteroalkyl group having between X and Y carbon atoms, for example a C1-C6 heteroalkyl group refers to a heteroalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to 1, 2, or 3 heteroatoms). Exemplary heteroalkyl groups include methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxymethyl, 2-methoxyethyl, 2-methoxyethoxy, (2-hydroxyethoxy)ethyl, (2- methoxyethoxy)ethyl, 3-hydroxy-2-(hydroxymethyl)propyl, 3-methoxy-2- (methoxymethyl)propyl, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, methanethiolato, ethanethiolato, or the like.

[0040] As used herein, the term “aryl” refers to an aromatic monocyclic or bicyclic ring system containing between 5 and 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl.

[0041] As used herein, the term “arylalkyl” refers to an alkyl group substituted with an aryl group. A CX-CY arylalkyl group refers to an arylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 arylalkyl group refers to an arylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with an aryl group. Exemplary arylalkyl groups include benzyl and phenethyl.

[0042] As used herein, the term “cycloalkyl” refers to a non-aromatic monocyclic ring system containing between 3 and 8 carbon atoms. A CX-CY cycloalkyl group (or an X- to Y- membered cycloalkyl group) refers to a cycloalkyl group having between X and Y carbon atoms, for example a C3-C6 cycloalkyl group (or a 3- to 6-membered cycloalkyl group) to refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like.

[0043] As used herein, the term “cycloalkylalkyl” refers to an alkyl group substituted with a cycloalkyl group. A CX-CY M- to N-membered cycloalkylalkyl group refers to a cycloalkylalkyl group having between X and Y carbon atoms in the alkyl chain and between M and N carbon atoms in the cycloalkyl ring, for example a C1-C3 3- to 6-membered cycloalkylalkyl group refers to a cycloalkylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a cycloalkyl group of 3, 4, 5, or 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0044] As used herein, the term “heteroaryl” refers to a cyclic aromatic group containing between 1 and 10 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the group contains between 5 and 10 carbon atoms or heteroatoms. Heteroaryl groups include those where a nitrogen atom of the heteroaryl ring is substituted with an oxide (-O-), for example, pyridinyl N-oxide and the like, where the context so permits. Heteroaryl groups may be monocyclic or bicyclic. As usedherein, the term “monocyclic heteroaryl” means a cyclic aromatic group containing 1 to 5 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more hetero atoms may be the same or different, wherein the monocyclic ring contains between 5 and 6 carbon atoms or heteroatoms. Exemplary heteroaryl groups include benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzotriazolyl, benzoxazolyl, furanyl, furazanyl, indolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, pyrrolo[2,3- b]pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrrolyl, 1,2,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,4-thiadiazolyl, thiazolyl, triazolyl, tetrazolyl, thiophenyl, and the like.

[0045] As used herein, the term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. A CX-CY heteroarylalkyl group refers to a heteroarylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 heteroarylalkyl group refers to a heteroarylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heteroaryl group. A “monocyclic heteroarylalkyl” group refers to an alkyl group substituted with a monocyclic heteroaryl group. Exemplary heteroarylalkyl groups include pyridylmethyl, pyrrolylmethyl, furanylmethyl, and the like.

[0046] As used herein, the term “heterocyclyl” refers to a non-aromatic (saturated or unsaturated) monocyclic group containing between 1 and 5 carbon atoms and between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the monocyclic ring contains between 3 and 6 carbon atoms or heteroatoms. Heterocyclyl groups include those where one or more carbon atoms of the heterocyclyl ring is substituted with an oxo (=O), for example, lactones, lactams, oxopyrrolidinyl, oxopiperidinyl, oxoimidazolidinyl, oxo-4,5- dihydrotetrazolyl, and the like; or a nitrogen atom of the heterocyclyl ring is substituted with an oxide (-O-), for example, pyrrolidinyl N-oxide, piperidinyl N-oxide, and the like, where the context so permits. An X- to Y-membered heterocyclyl group refers to a heterocyclyl group having between X and Y ring atoms (which may be carbon or heteroatoms). Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl,dithiolanyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, lactones, lactams, oxopyrrolidinyl, oxopiperidinyl, oxoimidazolidinyl, oxo-4,5-dihydrotetrazolyl, pyrrolidinyl N-oxide, piperidinyl N-oxide, and the like.

[0047] As used herein, the term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl group. A CX-CY heterocyclylalkyl group refers to a heterocyclylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3heterocyclylalkyl group refers to a heterocyclylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heterocyclyl group. Exemplary heterocyclylalkyl groups include piperidinylmethyl, pyrrolidinylmethyl, azetidinylmethyl, 2-(oxo-4,5- dihydrotetrazolyl)ethyl, and the like.

[0048] As used herein, the term “acyl” refers to a group attached through a carbonyl (- C(=O)-) linker, wherein the linker is bonded to an alkyl, hydroxy, alkoxy, amino, alkylamino, or dialkylamino group. A CX-CYacyl group refers to an acyl group wherein any alkyl, if present in the acyl group, has between X and Y carbon atoms, for example, a C1-C4acyl group refers to an acyl group selected from -C(=O)(C1-C4-alkyl), -C(=O)OH, -C(=O)O(C1-C4-alkyl), -C(=O)NH2, -C(=O)NH(C1-C4-alkyl), and -C(=O)N(C1-C4-alkyl)2.

[0049] As used herein, the term “sulfonyl” refers to a group attached through a sulfonyl (-S(=O)2-) linker, wherein the linker is bonded to an alkyl, amino, alkylamino, or dialkylamino group. A CX-CYsulfonyl group refers to a sulfonyl group wherein any alkyl, if present in the sulfonyl group, has between X and Y carbon atoms, for example, a C1-C4sulfonyl group refers to a sulfonyl group selected from -S(=O)2(C1-C4-alkyl), -S(=O)2NH2, -S(=O)2NH(C1-C4- alkyl), and -S(=O)2N(C1-C4-alkyl)2.

[0050] As used herein, the term “substituted” refers to a hydrogen radical of the designated moiety being replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise noted, a substituent can be in any position, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable as a pharmaceutical activecompound applies in general with respect to the definitions of all groups in the compounds of the formula I, and compounds of a subformula of formula I.

[0051] As used herein, the terms “independently” or “independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single compound.

[0052] As used herein, the term “unsubstituted” indicates that the respective group does not carry any of the specified non-hydrogen substituents.

[0053] As used herein, the term “pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid and base addition salts of a compound of formula I, or a compound of a subformula of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0054] As used herein, “ ” indicates the bond between two atoms may be either a single or a double bond. When is a single bond between two carbon atoms, the carbon atoms each are bonded to one more hydrogen atom (or substituent in place of a hydrogen atom) than if had been a double bond. Correspondingly, when is a double bond, the carbon atoms each are bonded to one fewer hydrogen atom (or substituent in place of a hydrogen atom) than if had been a single bond. If two bonds are adjacent, both bonds may be a single bond, either may be single and the other a double bond, but both bonds may not be a double bond.

[0055] If the compounds of the formula I, or compounds of a subformula of formula I, comprise one or more acidic or basic groups, for example basic heterocyclic groups, the corresponding physiologically or toxicologically acceptable salts are also included in the disclosure, especially the pharmaceutically acceptable salts. The compounds of the formula I, or compounds of a subformula of formula I, may thus be deprotonated on an acidic group and be used for example as alkali metal salts or as ammonium salts. Compounds of formula I, or compounds of a subformula of formula I, comprising at least one basic group may also be prepared and used in the form of their acid addition salts, for example in the form of pharmaceutically acceptable salts with inorganic acids and organic acids. Salts can in general be prepared from acidic and basic compounds of the formula I, or compounds of a subformula of formula I, by reaction with an acid or base in a solvent or diluent according to customaryprocedures. If the compounds of the formula I, or compounds of a subformula of formula I, simultaneously contain an acidic and a basic group in the molecule, the disclosure also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned. The present disclosure also comprises all salts of the compounds of the formula I, or compounds of a subformula of formula I, which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.

[0056] As used herein, the term “pharmaceutically acceptable excipient” refers to a non- toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present disclosure to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the subject. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0057] As used herein, the term “therapeutically effective amount” refers to an amount of a compound / composition according to the present disclosure effective in producing the desired therapeutic effect.

[0058] As used herein, the term “subject” refers to a human or animal subject. In some embodiments, the subject is human (i.e., a “patient”). In some embodiments, the subject is an animal.

[0059] As used herein, the term “compounds of formula I”, or “compounds of a subformula of formula I,” and equivalent expressions, include racemic compounds of formula I, or compound of a subformula of formula I, and their enantiomers, diastereoisomers, tautomers, atropisomers, and mixtures thereof, where the context so permits. Tautomeric compounds of formula I are exemplified by formulas I (tautomer 1) an I (tautomer 2).

[0060] Generally, in an imidazole with different substituents in the 3- and 4- position, substitution of the tautomeric proton, e.g., by alkylation, may generate a mixture of discrete regioisomers. For example, in the case of the alkylating agent is SEM-Cl, such a mixture will be referred to as “mixture of SEM-regioiosmers” herein.

[0061] As used herein, the term “subformula” refers to subsets of compound of formula I, such as compounds of formula I which are a compound of formula I-A, I-A1, I-A2, I-A3, I- A4, I-A5, I-A6, I-A7, I-B, I-B1, I-B2, I-B3, I-B4, I-B5, I-B6, I-B7, I-C, I-C1, I-C2, I-C3, I-D, I-D1, I-D2, I-D3, I-D4, I-D5, I-D6, I-D7, I-E, I-E1, I-E2, I-E3, I-E4, I-E5, I-E6, I-E7, I-F, I- F1, I-F2, I-F3, I-F4, I-F5, I-F6, I-F7, I-G1, I-G2, I-H, any one of I-J1 to I-J21, or any one of I- K1 to I-K8 where the context so permits.

[0062] As used herein, the term "isomers" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. The labels “isomer 1” and “isomer 2,” or the like, can be assigned to isomers of known absolute configuration or can be used to describe stereoisomers of unknown absolute configuration. Likewise, the labels “R*” or “S*” may be assigned to stereocenters of some enantiomeric compounds of unknown absolute configuration. The use of the labels “isomer 1,” “isomer 2,” R*, and S* is not to be interpreted as indicating that the absolute configuration of both isomers is known. The term “isomeric mixture” refers to a mixture of isomers.

[0063] As used herein, the term "stereoisomers" is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. The term “diastereomers” refers to stereoisomers that are not mirror images of one another and the term “enantiomers” refers to stereoisomers that are non-superimposable mirror images of each other. An enantiomer can be characterized by the absolute configurations of its asymmetriccenters, chiral axes and planes, and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer, individual diastereomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” A mixture containing any proportions of the diastereomers is called a “diastereomeric mixture”. For a compound with two chiral centers in a cyclic system, "trans" refers to the substituents (other than hydrogen) of the chiral centers are on opposite sides of the ring; "cis" refers to the substituents of the chiral centers are on the same sides of the ring. “Racemic trans” refers to equal proportions of two trans enantiomers and “racemic cis” refers to equal proportions of two cis enantiomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can also be directly separated using chiral chromatographic techniques or indirectly using enzymatic methods. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure.

[0064] One aspect of the present disclosure is a compound of formula Iwherein: A is selected fromeach is a single or a double bond, provided two adjacent are not both double bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; each instance of R3is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R4is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6 haloalkyl; R4P is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, - OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, - NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, - S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, monocyclic heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(arylene)R13, heterocyclyl, or -(heterocyclylene)R13; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, - OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, or -NR9S(=O)2NR11R12; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or more R13; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or more R13; each instance of R13is independently selected from halogen, C1-C4alkyl, C1-C4haloalkyl, -OH, -O(C1-C4alkyl), -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), - C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4alkyl), -OC(=O)N(C1-C4alkyl)(C1-C4alkyl), - NHC(=O)(C1-C4alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4alkyl)(C1-C4alkyl), -(CH2)qC(=O)(C1-C4alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a heterocyclyl ring; X1 is halogen; m is 0 or 1; n is 1 or 2; each p is independently 1, 2, or 3; and each q is independently 1, 2, or 3; wherein when, R4 and R5 may be taken together with the carbons connecting them to form a 5- or 6-membered heterocyclyl ring; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,provided the compound of formula I is not of formula.

[0065] One embodiment is a compound of formula I, wherein: A is selected fromR1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R2 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3haloalkyl; each instance of R3is independently selected from halogen, -OR11, -NR11R12, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl;R4is selected from halogen, -OR11, -NR11R12, C1-C4alkyl, C1-C4heteroalkyl, and C1- C3haloalkyl; R4P is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -SR7, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O- )R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(phenylene)R13, 4- to 6- membered heterocyclyl, or -(4- to 6-membered heterocyclene)R13; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13;each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13is independently selected from halogen, C1-C4alkyl, C1-C4haloalkyl, -OH, -O(C1-C4alkyl), -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4alkyl), -NHC(=O)N(C1-C4alkyl)(C1-C4alkyl), -N(C1-C4alkyl)C(=O)(C1- C4alkyl), -N(C1-C4alkyl)C(=O)OH, -N(C1-C4alkyl)C(=O)O(C1-C4alkyl), -N(C1-C4alkyl)C(=O)NH2, -N(C1-C4alkyl)C(=O)NH(C1-C4alkyl), -N(C1-C4alkyl)C(=O)N(C1-C4alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4- to 6-membered heterocyclyl ring; m is 0 or 1; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0066] One embodiment is a compound of formula I, wherein: A is selected fromR1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, - NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pC(=O)OR11, -(CH2)p(phenylene)R13, or –(4- to 6- membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10; each instance of R9is independently selected from hydrogen and C1-C4alkyl;each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, C3- C6cycloalkyl, 4- to 6-membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4sulfonyl provided R11is not C1-C4sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -OC(=O)(C1-C4 alkyl), -OC(=O)O(C1-C4 alkyl), -(CH2)qOH, and - S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4-membered heterocyclyl ring; m is 0; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0067] One embodiment is a compound of formula I, wherein: A is selected fromR1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro, chloro, and methyl; R4Pis selected from hydrogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, - (CH2)OR11, -(CH2)C(=O)OR11, -(CH2)(phenylene)R13, or –(4- to 6-membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, 4 to 6-membered heterocyclyl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, or -C(=O)NR11R12,; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, C3- C6cycloalkyl, 4- to 6- membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13;each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33- to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, -C(=O)OtBu, -OC(=O)Me, -OC(=O)OMe, -OC(=O)OEt, -(CH2)OH, and -S(=O)2(Me), and wherein two R13groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form:; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0068] One embodiment is a compound of formula I which is a compound of formula I-A, I-A wherein R1, R2, R3, R4, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0069] One embodiment is a compound of formula I which is a compound of formula I-A, wherein: R1is selected from halogen; R2is selected from halogen and C1-C4alkyl;R4is selected from halogen and C1-C4alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0070] One embodiment is a compound of formula I which is a compound of formula I-A, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0071] One embodiment is a compound of formula I which is a compound of formula I-A1 ,wherein R1, R2, R4, and R5are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0072] One embodiment is a compound of formula I which is a compound of formula I- A1, wherein R1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl;R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0073] One embodiment is a compound of formula I which is a compound of formula I- A1, wherein: R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0074] One embodiment is a compound of formula I which is a compound of formula I-A2, I-A2 wherein: each instance of X is independently selected from halogen; and R5is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0075] One embodiment is a compound of formula I which is a compound of formula I- A2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen,C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0076] One embodiment is a compound of formula I which is a compound of formula I- A2, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0077] One embodiment is a compound of formula I which is a compound of formula I-A3 ,wherein R5is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0078] One embodiment is a compound of formula I which is a compound of formula I- A3, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0079] One embodiment is a compound of formula I which is a compound of formula I- A3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0080] One embodiment is a compound of formula I which is a compound of formula I-A4, I-A4 wherein: L is selected from -R6and -NR7R8; and R1, R2, R4, R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0081] One embodiment is a compound of formula I which is a compound of formula I- A4, wherein R1is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0082] One embodiment is a compound of formula I which is a compound of formula I- A4, wherein R1is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0083] One embodiment is a compound of formula I which is a compound of formula I-A5 ,wherein: each instance of X is independently selected from halogen; L is selected from -R6and -NR7R8; and R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0084] One embodiment is a compound of formula I which is a compound of formula I- A5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0085] One embodiment is a compound of formula I which is a compound of formula I- A5, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0086] One embodiment is a compound of formula I which is a compound of formula I-A6 ,wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4, R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0087] One embodiment is a compound of formula I which is a compound of formula I- A6, wherein R1is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4 is selected from halogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0088] One embodiment is a compound of formula I which is a compound of formula I- A6, wherein R1is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0089] One embodiment is a compound of formula I which is a compound of formula I-A7, I-A7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0090] One embodiment is a compound of formula I which is a compound of formula I- A7, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0091] One embodiment is a compound of formula I which is a compound of formula I- A7, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0092] One embodiment is a compound of formula I which is a compound of formula I-B ,wherein R1, R2, R3, R4, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0093] One embodiment is a compound of formula I which is a compound of formula I-B, wherein: R1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0094] One embodiment is a compound of formula I which is a compound of formula I-B, wherein: R1 is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4is selected from fluoro and chloro; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; m is 0; and n is 1;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0095] One embodiment is a compound of formula I which is a compound of formula I-B, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound. For example, a compound of formula, wherein R1, R2, R7, and n are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0096] One embodiment is a compound of formula I which is a compound of formula I-B1 ,wherein R1, R2, R4, and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0097] One embodiment is a compound of formula I which is a compound of formula I- B1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0098] One embodiment is a compound of formula I which is a compound of formula I- B1, wherein: R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4is selected from fluoro and chloro;R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0099] One embodiment is a compound of formula I which is a compound of formula I- B1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4and R5are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound. For example, a compound of formula, wherein R1, R2, and R7 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0100] One embodiment is a compound of formula I which is a compound of formula I-B2 ,wherein: each instance of X is independently selected from halogen; and R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0101] One embodiment is a compound of formula I which is a compound of formula I- B2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclicheteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0102] One embodiment is a compound of formula I which is a compound of formula I- B2, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0103] One embodiment is a compound of formula I which is a compound of formula I-B3,I-B3 wherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0104] One embodiment is a compound of formula I which is a compound of formula I- B3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted orsubstituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0105] One embodiment is a compound of formula I which is a compound of formula I- B3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0106] One embodiment is a compound of formula I which is a compound of formula I-B4, I-B4 wherein: L is selected from -R6and -NR7R8; and R1, R2, R4, R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0107] One embodiment is a compound of formula I which is a compound of formula I- B4, wherein R1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0108] One embodiment is a compound of formula I which is a compound of formula I- B4, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0109] One embodiment is a compound of formula I which is a compound of formula I- B4, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and L are joined, such that hydrogenother radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound. For example, a compound of formula, wherein R1, R2, and R7are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0110] One embodiment is a compound of formula I which is a compound of formula I-B5, I-B5 wherein: each instance of X is independently selected from halogen; L is selected from -R6and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0111] One embodiment is a compound of formula I which is a compound of formula I- B5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0112] One embodiment is a compound of formula I which is a compound of formula I- B5, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0113] One embodiment is a compound of formula I which is a compound of formula I-B6 ,wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4, R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0114] One embodiment is a compound of formula I which is a compound of formula I- B6, wherein R1is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl;R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0115] One embodiment is a compound of formula I which is a compound of formula I- B6, wherein R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4is selected from fluoro and chloro; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12;each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0116] One embodiment is a compound of formula I which is a compound of formula I-B7 ,wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0117] One embodiment is a compound of formula I which is a compound of formula I- B7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen,C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0118] One embodiment is a compound of formula I which is a compound of formula I- B7, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0119] One embodiment is a compound of formula I which is a compound of formula I-C ,wherein R1, R2, R3, X1, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0120] One embodiment is a compound of formula I which is a compound of formula I-C, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R3 is selected from halogen and C1-C4 alkyl; m is 0 or 1; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0121] One embodiment is a compound of formula I which is a compound of formula I-C, wherein R1 is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R3is selected from fluoro, chloro, and methyl; X1is selected from fluoro and chloro;m is 1; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0122] One embodiment is a compound of formula I which is a compound of formula I-C1, I-C1 wherein R1, R2, R3, X1, and m are as defined for a compound of formula I; and or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0123] One embodiment is a compound of formula I which is a compound of formula I- C1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0124] One embodiment is a compound of formula I which is a compound of formula I- C1, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R3 is selected from fluoro, chloro, and methyl; X1is selected from fluoro and chloro; and m is 1;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0125] One embodiment is a compound of formula I which is a compound of formula I-C2, I-C2 wherein each instance of X is independently selected from halogen; and R3, X1, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0126] One embodiment is a compound of formula I which is a compound of formula I- C2, wherein R3is selected from halogen and C1-C4alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0127] One embodiment is a compound of formula I which is a compound of formula I- C2, wherein each instance of X is independently selected from fluoro, chloro, and bromo; R3is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0128] One embodiment is a compound of formula I which is a compound of formula I-C3, I-C3 wherein R3, X1, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0129] One embodiment is a compound of formula I which is a compound of formula I- C3, wherein R3is selected from halogen and C1-C4alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0130] One embodiment is a compound of formula I which is a compound of formula I- C3, wherein each instance of X is independently selected from fluoro, chloro, and bromo; R3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0131] One embodiment is a compound of formula I which is a compound of formula I-D,I-D wherein R1, R2, R3, R4P, R5, n, m, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0132] One embodiment is a compound of formula I which is a compound of formula I-D, wherein: R1is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0133] One embodiment is a compound of formula I which is a compound of formula I-D, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0134] One embodiment is a compound of formula I which is a compound of formula I-D1, I-D1wherein R1, R2, R4P, R5, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0135] One embodiment is a compound of formula I which is a compound of formula I- D1, wherein R1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0136] One embodiment is a compound of formula I which is a compound of formula I- D1, wherein: R1 is fluoro;R2is selected from chloro, bromo, methyl, and ethyl; R4Pis selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0137] One embodiment is a compound of formula I which is a compound of formula I-D2, I-D2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and R5 and are as defined for a compound of formula I;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0138] One embodiment is a compound of formula I which is a compound of formula I- D2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0139] One embodiment is a compound of formula I which is a compound of formula I- D2, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6;R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0140] One embodiment is a compound of formula I which is a compound of formula I-D3, I-D3 wherein R5and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0141] One embodiment is a compound of formula I which is a compound of formula I- D3, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6;R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0142] One embodiment is a compound of formula I which is a compound of formula I- D3, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12;each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0143] One embodiment is a compound of formula I which is a compound of formula I-D4, I-D4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0144] One embodiment is a compound of formula I which is a compound of formula I- D4, wherein R1is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0145] One embodiment is a compound of formula I which is a compound of formula I- D4, wherein R1is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0146] One embodiment is a compound of formula I which is a compound of formula I-D5, I-D5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4alkyl; and L is selected from -R6and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0147] One embodiment is a compound of formula I which is a compound of formula I- D5, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted orsubstituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0148] One embodiment is a compound of formula I which is a compound of formula I- D5, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0149] One embodiment is a compound of formula I which is a compound of formula I-D6, I-D6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0150] One embodiment is a compound of formula I which is a compound of formula I- D6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0151] One embodiment is a compound of formula I which is a compound of formula I- D6, wherein R1is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0152] One embodiment is a compound of formula I which is a compound of formula I-D7, I-D7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0153] One embodiment is a compound of formula I which is a compound of formula I- D7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0154] One embodiment is a compound of formula I which is a compound of formula I- D7, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0155] One embodiment is a compound of formula I which is a compound of formula I-E, I-E wherein R1, R2, R3, R4P, R5, n, m, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0156] One embodiment is a compound of formula I which is a compound of formula I-E, wherein: R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl;each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0157] One embodiment is a compound of formula I which is a compound of formula I-E, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0158] One embodiment is a compound of formula I which is a compound of formula I-E1, I-E1 wherein R1, R2, R4P, R5, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0159] One embodiment is a compound of formula I which is a compound of formula I- E1, wherein R1is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0160] One embodiment is a compound of formula I which is a compound of formula I- E1, wherein: R1is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0161] One embodiment is a compound of formula I which is a compound of formula I-E2, I-E2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4alkyl; and R5and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0162] One embodiment is a compound of formula I which is a compound of formula I- E2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0163] One embodiment is a compound of formula I which is a compound of formula I- E2, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0164] One embodiment is a compound of formula I which is a compound of formula I-E3, I-E3 wherein R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0165] One embodiment is a compound of formula I which is a compound of formula I- E3, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0166] One embodiment is a compound of formula I which is a compound of formula I- E3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0167] One embodiment is a compound of formula I which is a compound of formula I-E4, I-E4 wherein L is selected from -R6 and -NR7R8; andR1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0168] One embodiment is a compound of formula I which is a compound of formula I- E4, wherein R1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0169] One embodiment is a compound of formula I which is a compound of formula I- E4, wherein R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl;R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0170] One embodiment is a compound of formula I which is a compound of formula I-E5, I-E5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; L is selected from -R6and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0171] One embodiment is a compound of formula I which is a compound of formula I- E5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0172] One embodiment is a compound of formula I which is a compound of formula I- E5, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0173] One embodiment is a compound of formula I which is a compound of formula I-E6, I-E6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0174] One embodiment is a compound of formula I which is a compound of formula I- E6, wherein R1is selected from halogen; R2 is selected from halogen and C1-C4 alkyl;R4Pis selected from hydrogen and C1-C4alkyl; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0175] One embodiment is a compound of formula I which is a compound of formula I- E6, wherein R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4Pis selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0176] One embodiment is a compound of formula I which is a compound of formula I-E7, I-E7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0177] One embodiment is a compound of formula I which is a compound of formula I- E7, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen,C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0178] One embodiment is a compound of formula I which is a compound of formula I- E7, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0179] One embodiment is a compound of formula I which is a compound of formula I-F, I-F wherein R1, R2, R3, R4P, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0180] One embodiment is a compound of formula I which is a compound of formula I-F, wherein: R1 is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted orsubstituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0181] One embodiment is a compound of formula I which is a compound of formula I-F, wherein: R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom;m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0182] One embodiment is a compound of formula I which is a compound of formula I-F1, I-F1 wherein R1, R2, R4P, and R5are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0183] One embodiment is a compound of formula I which is a compound of formula I- F1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted orsubstituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0184] One embodiment is a compound of formula I which is a compound of formula I- F1, wherein: R1 is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4Pis selected from hydrogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0185] One embodiment is a compound of formula I which is a compound of formula I-F2, I-F2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4alkyl; and R5is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0186] One embodiment is a compound of formula I which is a compound of formula I- F2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0187] One embodiment is a compound of formula I which is a compound of formula I- F2, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0188] One embodiment is a compound of formula I which is a compound of formula I-F3,wherein R5is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0189] One embodiment is a compound of formula I which is a compound of formula I- F3, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0190] One embodiment is a compound of formula I which is a compound of formula I- F3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0191] One embodiment is a compound of formula I which is a compound of formula I-F4, I-F4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, and R8 are as defined for a compound of formula I;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0192] One embodiment is a compound of formula I which is a compound of formula I- F4, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4Pis selected from hydrogen and C1-C4alkyl; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0193] One embodiment is a compound of formula I which is a compound of formula I- F4, wherein R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4Pis selected from hydrogen and methyl;R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0194] One embodiment is a compound of formula I which is a compound of formula I-F5, I-F5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4alkyl; and L is selected from -R6 and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0195] One embodiment is a compound of formula I which is a compound of formula I- F5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0196] One embodiment is a compound of formula I which is a compound of formula I- F5, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0197] One embodiment is a compound of formula I which is a compound of formula I-F6, I-F6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0198] One embodiment is a compound of formula I which is a compound of formula I- F6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl;R4Pis selected from hydrogen and C1-C4alkyl; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0199] One embodiment is a compound of formula I which is a compound of formula I- F6, wherein R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; R4Pis selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C4alkyl, and C1-C4heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0200] One embodiment is a compound of formula I which is a compound of formula I-F7, I-F7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0201] One embodiment is a compound of formula I which is a compound of formula I- F7, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen,C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0202] One embodiment is a compound of formula I which is a compound of formula I- F7, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0203] One embodiment is a compound of formula I which is a compound of formula I-G1 ,wherein: L1is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; j is 0, 1, or 2; and R10, R11, R12, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0204] One embodiment is a compound of formula I which is a compound of formula I-G2, I-G2wherein: L1is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; j is 0, 1, or 2; and R10, R11, and R12 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0205] One embodiment is a compound of formula I which is a compound of formula I-H ,wherein: R1, R2, R4P, and R6are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0206] One embodiment is a compound of formula I which is a compound of formula I-H, wherein: R1 is fluoro; R2is chloro; R4Pis methyl; R6is C1-C6alkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6- membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, - OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)OR11, - (CH2)NR11R12, -(CH2)C(=O)R10, -(CH2)C(=O)OR11, -(CH2)C(=O)NR11R12, - (CH2)p(phenylene)R13, 4- to 6-membered heterocyclyl, or –(4- to 6-membered heterocyclene)R13; and R10, R11, R12, and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0207] One embodiment is a compound of formula I which is a compound of formula I-H, wherein: R1 is fluoro; R2 is chloro; R4P is methyl; R6is C1-C6alkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6- membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three C1-C4alkyl, -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)OR11, -NR9C(=O)R10, - NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -NR9S(=O)2R10, -(CH2)C(=O)OR11, - (CH2)(phenylene)R13, or -(4- to 6-membered heterocyclene)R13; and R10, R11, R12, and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0208] In other embodiments, a compound of formula I is a compound of any one of formulas I-J1 to I-J5:wherein: z is 0, 1, or 2 where valency permits; each instance of Z1is independently selected from halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, - S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, - (CH2)p(arylene)R13, heterocyclyl, and -(heterocyclene)R13; each instance of E1is independently selected from -CH- and -N-; E2is selected from -NH-, -O-, and -S-; E3is selected from -CH2-,-NH-, and -O-; and R1, R2, R4P, R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0209] In other embodiments, a compound of formula I is a compound of any one of formulas I-J1 to I-J5, wherein: R1is fluoro; R2is chloro; R4P is methyl; z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from halogen, C1-C4 alkyl, -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)OR11, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -NR9S(=O)2R10, -(CH2)C(=O)OR11, - (CH2)(phenylene)R13, and -(4- to 6-membered heterocyclene)R13; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0210] In other embodiments, a compound of formula I is a compound of any one of formulas I-J1 to I-J5, wherein: R1 is fluoro; R2 is chloro; R4Pis methyl; z is 0, 1, or 2 where valency permits; each instance of Z1is independently selected from chloro, C1-C4alkyl, -OH, -O(C1-C4alkyl), -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 heteroalkyl), -NH(C3-C6 cycloalkyl), -C(=O)Me, - C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)OtBu, -C(=O)NH2, -OC(=O)O(C1-C4 alkyl), - NHC(=O)Me, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, -S(=O)2Me, -NHS(=O)2Me, - CH2C(=O)OH, -(CH2)C(=O)O(C1-C4 alkyl), -(CH2)(phenylene)R13, or -(4- to 6-membered heterocyclene)R13; wherein if z is 2, the second instance of Z1is C1-C4alkyl; each instance of E1is independently selected from -CH- and -N-; E2is selected from -NH-, -O-, and -S-; E3is selected from -CH2-,-NH-, and -O-; and R13 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0211] In other embodiments, a compound of formula I is a compound of any one of formulas I-K1 to I-K8:wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R1, R2, R4P, R9, R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0212] In other embodiments, a compound of formula I is a compound of any one of formulas I-K1 to I-K8, wherein: R1 is fluoro; R2 is chloro; R4Pis methyl; y is 0, 1, or 2 where valency permits; each instance of E1is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and each instance of R9 is H; each instance of R10 is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl; which groups are unsubstituted or substituted with one or two R13; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; and R13is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0213] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is selected from halogen and C1-C4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0214] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is fluoro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0215] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0216] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is selected from chloro, bromo, methyl, and ethyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0217] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is chloro;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0218] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is selected from halogen and C1-C4 alkyl; R2is selected from chloro, bromo, methyl, and ethyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0219] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1is fluoro; R2is selected from chloro, bromo, methyl, and ethyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0220] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1is fluoro; R2is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0221] One embodiment is a compound of formula I, wherein:; R4is selected from halogen and C1-C4alkyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0222] One embodiment is a compound of formula I, wherein:; R4is selected from fluoro, chloro, and methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0223] One embodiment is a compound of formula I, wherein:; R4is chloro; and m is 0;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0224] One embodiment is a compound of formula I, wherein:X1is selected from halogen; R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0225] One embodiment is a compound of formula I, wherein:X1 is selected from fluoro and chloro; R3is selected from fluoro, chloro, and methyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0226] One embodiment is a compound of formula I, wherein:X1is selected from fluoro and chloro; R3 is selected from fluoro, chloro, and methyl; andm is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0227] One embodiment is a compound of formula I, wherein:R4P is selected from hydrogen and C1-C4 alkyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0228] One embodiment is a compound of formula I, wherein:R4P is selected from hydrogen and methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0229] One embodiment is a compound of formula I, wherein:R4P is methyl; and m is 0;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0230] One embodiment is a compound of formula I, wherein: A is selected from; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0231] One embodiment is a compound of formula I, wherein:; R5 is selected from -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; and R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0232] One embodiment is a compound of formula I, wherein:R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen,C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0233] One embodiment is a compound of formula I, wherein:R5 is selected from -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1- C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0234] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F,,.

[0236] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, or I-F6, wherein R5 is selected from ,, , ,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0237] All these subgroups taken alone or in combination are part of the description.

[0238] One embodiment is a compound of formula I, selected from the compounds listed in Table 1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0239] One embodiment is a compound of formula I, selected from: Methyl 3-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanoate; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propan-1-ol; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanoic acid; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanamide; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)-N-methylpropanamide; Methyl N-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)-N-methylglycinate; (3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2- hydroxyethyl)-N,3-dimethylpiperidine-1-sulfonamide; N-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)-N-methylglycine; 2-((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3- dimethylpiperidine-1-sulfonamido)acetamide; 2-((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3- dimethylpiperidine-1-sulfonamido)-N-methylacetamide; Methyl (S*)-3-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propanoate;(S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propan-1-ol; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propanoic acid; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propanamide; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)-N-methylpropanamide; Methyl (S*)-N-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)-N-methylglycinate; (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2-hydroxyethyl)-N,3- dimethyl-3,6-dihydropyridine-1(2H)-sulfonamide; (S*)-N-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)-N-methylglycine; (S*)-2-(4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3-dimethyl-1,2,3,6- tetrahydropyridine-1-sulfonamido)acetamide; (S*)-2-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3-dimethyl- 1,2,3,6-tetrahydropyridine)-1-sulfonamido)-N-methylacetamide; (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxamide; 3-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)propan-1-ol; and 3-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)propanoic acid; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0240] One embodiment is a compound of formula I, or a compound of a subformula of formula I, that has sufficient solubility to avoid, for example, advanced formulations or advanced delivery systems, which include but are not limited to liposomal suspensions, inclusion complexes solid dispersions in polymers mechano-chemically activated systems,microparticles or nanoparticles, micro- or nano-emulsions, and vesicular systems. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 20 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 100 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 500 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 1000 µM or greater at pH 7.4.

[0241] The compounds of formula I, and subformulas thereof, may comprise one or more asymmetric atoms and / or chiral axes. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures are provided herein.

[0242] Some of the compounds of formula I, and subformulas thereof, may exist in the form of acids or of base-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable bases or cations, but the salts of other bases or cations that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure.

[0243] Some of the compounds of formula I, and subformulas thereof, may exist in the form of bases or of acid-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable acids or anions, but the salts of other acids or anions that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure.

[0244] Another aspect of the present disclosure is a process for preparing a compound of formula I, or a subformula thereof, comprising reacting an intermediate of formula B*-PG with an intermediate of formula D1 in the presence of a catalyst and a base to give an intermediate of formula C2:wherein R1, A, and n are as defined for a compound of formula I, R2*is as defined for a compound of formula I or hydrogen, PG is a protecting group, and X is selected from halogen. C2 may be obtained as a mixture of positional isomers, where A is adjacent to the protected nitrogen atom in a first isomer and not adjacent to the protected nitrogen isomer in a second isomer. In some embodiments, the protecting group is 2-(trimethylsilyl)ethoxymethyl. In some embodiments, the catalyst is selected from bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) and bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2). In some embodiments, the base is selected from potassium carbonate, potassium acetate, and sodium carbonate. In some embodiments, the protecting group is 2- (trimethylsilyl)ethoxymethyl, the catalyst is selected from Pd(dtbpf)Cl2and Pd(dppf)Cl2, and the base is selected from potassium carbonate, potassium acetate, and sodium carbonate. In some embodiments, an intermediate of formula C2 is subsequently deprotected to give a compound of formula I. In some embodiments, an intermediate of formula C2, wherein R2*is hydrogen is subsequently halogenated and deprotected to give a compound of formula I, wherein R2is selected from halogen.

[0245] Yet another aspect of the present disclosure is a pharmaceutical composition that includes a compound described herein as an active ingredient. These pharmaceutical compositions comprise a therapeutically effective amount of a compound of formula I, or acompound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0246] The said excipients may be selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0247] In these pharmaceutical compositions for oral, inhalative, topical, or transdermal administration, the active ingredient of formula I, or a compound of a subformula of formula I, or its pharmaceutically acceptable salt, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals or to human beings for the treatment of a disease, disorder, or condition.

[0248] Appropriate unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, forms for inhalative administration, and forms for topical or transdermal administration. For topical and transdermal administration, it is possible to use the herein described compounds in creams, gels, ointments, or lotions.

[0249] By the oral route, the dose of active principle per day may reach 2000 mg / day, taken all at once or in portions. By the inhalative route, the dose of active principle per day may reach 50 mg / day. By parenteral routes, the dose of active principle per day may reach 400 mg / day.

[0250] There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the disclosure. According to usual practice, the dosage that is appropriate for each subject is determined by the doctor according to the mode of administration and the weight and response of the said subject.

[0251] Compounds described herein have an antagonistic activity for MRGPRX2. The compounds according to the present disclosure can, therefore, be used for preparing medicaments, especially medicaments which are antagonists of MRGPRX2.

[0252] Accordingly, yet another aspect of the present disclosure is a medicament, characterized in that it comprises a compound of formula I, or a compound of a subformula offormula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0253] The medicaments of the present disclosure can be employed therapeutically, especially in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders. In yet another aspect, also provided is the use of a compound of formula I, or a compound of a subformula of formula I, for preparing a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

[0254] In one embodiment, the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain.

[0255] In one embodiment, the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma. In one embodiment, the disease, disorder, or condition is atopic dermatitis. In one embodiment, the disease, disorder, or condition is chronic spontaneous urticaria. In one embodiment, the disease, disorder, or condition is prurigo nodularis. In one embodiment, the disease, disorder, or condition is asthma.

[0256] Yet another aspect of the present disclosure is a method of treating a disease, disorder, or condition associated with MRGPRX2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0257] One embodiment is a method for treating a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0258] One embodiment is a method for treating a disease, disorder, or condition for which modulation of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof.

[0259] One embodiment is a method for treating a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0260] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, mast cell disorders, pain disorders, and itch disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0261] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis systemic mastocytosis cutaneous mastocytosis, mastocyticenterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0262] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0263] One embodiment is a method for treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0264] One embodiment is a method for treating chronic spontaneous urticaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0265] One embodiment is a method for treating prurigo nodularis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0266] One embodiment is a method for treating asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof.

[0267] According to another aspect, also provided is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease disorder or condition associated with MRGPRX2.

[0268] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation.

[0269] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which modulation of MRGPRX2 is indicated. Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof.

[0270] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated.

[0271] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

[0272] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction allergy rheumatoid arthritis inflammatory bowel disease,ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain.

[0273] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.

[0274] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.

[0275] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic spontaneous urticaria.

[0276] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of prurigo nodularis.

[0277] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma.

[0278] One embodiment is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula I is selected from the compounds listed in Table 1.

[0279] One embodiment is a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof or a mixture thereof or a pharmaceutically acceptable saltthereof, for use as a medicament, wherein the compound of formula I is selected from one of the above three lists.

[0280] One embodiment is the use of a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from one of the above three lists.

[0281] One embodiment is a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from one of the above three lists.

[0282] One embodiment is a method of treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from one of the above three lists.

[0283] GENERAL SYNTHETIC METHODS

[0284] The compounds of formula I herein can be prepared by the methods outlined in the following reaction schemes and examples. In the schemes and examples, the addition of a protecting group (PG) to an imidazole ring nitrogen may lead to positional isomers, which are depicted herein as two structures. A given substituent on the adjacent carbon atoms of the imidazole ring may be either adjacent or not adjacent to the protected nitrogen atom. Becauseprotected imidazoles do not typically tautomerize, these intermediates may be prepared, isolated, characterized, and modified as a mixture of discrete positional isomers. After removal of the protecting group, the imidazole ring of the resulting intermediate or compound of formula I will no longer be restricted from tautomerization and may no longer exist as discrete positional isomers or a mixture thereof.

[0285] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 1.

[0287] In Scheme 1, each X is independently selected from halogen. Carbamimidoyl pyridine intermediates of formula A1 may be commercially available, such as 5- fluoropyridine-2-carboxamidine, or can be prepared according to Scheme 5 or by methods known to those skilled in the art. Haloacetyl intermediates of formula A2 may be commercially available or can be prepared by methods known to those skilled in the art. A carbamimidoyl pyridine intermediate of formula A1 can be cyclized to a pyridyl-imidazole intermediate of formula A3 by reacting with a haloacetyl intermediate of formula A2 in the presence of a base, such as potassium carbonate, in a solvent, such as ethanol. The pyridyl- imidazole intermediate of formula A3 can be converted to a compound of formula I, wherein R2 is selected from halogen (e.g., -Cl), by reacting with a halogenation reagent, such as N- chlorosuccinimide, in a solvent such as DMF.

[0288] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Schemes 2-6. Schemes 2-6 depict methods of preparing different pyridyl-imidazole halide intermediates which can be coupled with boronic ester intermediates to give compounds of formula I or other intermediates which can be converted to compounds of formula I.

[0290] Picolinaldehyde intermediates of formula B1 may be commercially available, such as 5-fluoropicolinaldehyde, or can be prepared by methods known to those skilled in the art. A picolinaldehyde intermediate of formula B1 can be converted to a pyridyl-imidazole intermediate of formula B2 by reacting with oxalaldehyde and ammonium hydroxide in a solvent, such as ethanol. The pyridyl-imidazole intermediate of formula B2 can be converted to a protected pyridyl-imidazole intermediate of formula B3 by addition of a protecting groupto the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.

[0291] A protected pyridyl-imidazole intermediate of formula B3 can be converted to a protected pyridyl-imidazole bromide intermediate of formula B4 (an isomeric mixture) by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as chloroform.

[0292] A protected pyridyl imidazole intermediate of formula B2 can be converted to a pyridyl-imidazole dibromide intermediate of formula B5 by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as chloroform. The pyridyl-imidzole dibromide intermediate of formula B5 can be converted to a protected pyridyl-imidazole dibromide intermediate of formula B6 by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.

[0293] Scheme 3

[0294] Pyridyl-imidazole intermediates of formula B2 can be prepared according to Scheme 2. A pyridyl-imidazole intermediate of formula B2 can be converted to a pyridyl- imidazole chloride intermediate of formula B7 by reacting with a chlorination reagent, such as N-chlorosuccinimide, in a solvent, such as DMF. The pyridyl-imidazole chloride intermediate of formula B7 can be converted to a pyridyl-imidazole chloride bromide intermediate of formula B8 by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as THF. The pyridyl-imidazole chloride bromide intermediate of formula B8 can be converted to a protected pyridyl-imidazole chloride bromide intermediate of formula B9 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.

[0295] Scheme 4

[0296] Pyridyl-imidazole intermediates of formula B2 can be prepared according to Scheme 2. A pyridyl-imidazole intermediate of formula B2 can be converted to a pyridyl- imidazole diiodide intermediate of formula B10 by reacting with an iodination reagent, such asN-iodosuccinimide, in a solvent, such as acetonitrile. The pyridyl-imidazole diiodide intermediate of formula B10 can be converted to a pyridyl-imidazole iodide intermediate of formula B11 by reacting with a reducing agent, such as sodium sulfite (Na2SO3), in the presence of water, in a solvent such as DMF, water, or a mixture thereof. The pyridyl- imidazole iodide intermediate of formula B11 can be converted to a protected pyridyl- imidazole iodide intermediate of formula B12 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF. The protected pyridyl-imidazole iodide intermediate of formula B12 (an isomeric mixture) can be converted to a protected pyridyl-imidazole chloride iodide intermediate of formula B13 (an isomeric mixture) by reacting with a chlorination reagent, such as N-chlorosuccinimide.

[0297] Scheme 5

[0298] Picolinonitrile intermediates of formula A0 may be commercially available, such as 5-methyl-picolinonitrile, or may be prepared by methods known to those skilled in the art. A picolinonitrile intermediate of formula A0 can be converted to a carbamimidoyl pyridine intermediate of formula A1 by reacting with a base, such as LiHMDS, in a solvent such as THF, and quenching with ammonium chloride.

[0299] Haloacetyl intermediates of formula D2 may be commercially available, such as when R2is methyl or ethyl, or can be prepared by methods known to those skilled in the art. A carbamimidoyl pyridine intermediate of formula A1 can be converted to a pyridyl-imidazole intermediate of formula B14 by reacting with a haloacetyl intermediate of formula D2 in the presence of a base, such as potassium carbonate, in a solvent, such as ethanol. A pyridyl- imidazole intermediate of formula B14 can be converted to a pyridyl-imidazole bromide intermediate of formula B15 by reacting with a bromination reagent, such as N- bromosuccinimide, in a solvent, such as acetonitrile. A pyridyl-imidazole bromide intermediate of formula B15 can be converted to a protected pyridyl-imidazole bromide intermediate of formula B16 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.

[0300] Scheme 6

[0301] Picolinaldehyde intermediates of formula B1 may be commercially available, such as 5-fluoropicolinaldehyde, or can be prepared by methods known to those skilled in the art. An oxoacetyl intermediate of formula D13 may be commercially available, such as wherein R2 is methyl or ethyl, or can be prepared by methods known to those skilled in the art. A picolinaldehyde intermediate of formula B1 can be converted to a pyridyl-imidazole intermediate of formula B17 by reacting with an oxoacetyl intermediate of formula D13 in the presence of ammonium acetate in a solvent, such as methanol. A pyridyl-imidazole intermediate of formula B17 can be converted to a pyridyl-imidazole iodide intermediate of formula B18 by reacting with an iodination reagent, such as N-iodosuccinimide, in a solvent, such as acetonitrile. A pyridyl-imidazole iodide intermediate of formula B18 can be converted to a protected pyridyl-imidazole iodide intermediate of formula B19 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such assodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.

[0302] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 7, which depicts the coupling of various pyridyl-imidazole halide intermediates (such as those prepared according to Schemes 2-6) with a boronic acid intermediate. In Scheme 7, R2* is R2 as defined for a compound of formula I, but may also be selected from hydrogen.

[0303] Scheme 7

[0304] Intermediates of formula B* are non-protected pyridyl-imidazoles including intermediates of formula B5, B7, B8, B10, B11, B15, and B18, which can be prepared according to Schemes 2-6. Intermediates of formula B*-PG are protected pyridyl-imidazolesincluding intermediates of formula B4, B6, B9, B12, B13, B16, and B19, which can be prepared according to Schemes 2-6.

[0305] An intermediate of formula B* can be converted to an intermediate of formula C1 (which may also be a compound of formula I) by coupling with a boronic acid intermediate of formula D1, which may be commercially available or can be prepared by methods known to those skilled in the art. The coupling can be accomplished in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and a base, such as potassium carbonate, potassium acetate, or sodium carbonate, in a solvent, such as NMP, DMF, dioxane, or DMSO, or a mixture with water thereof.

[0306] An intermediate of formula B*-PG (an isomeric mixture) can be converted to an intermediate of formula C2 (an isomeric mixture) by coupling with a boronic acid intermediate of formula D1, which may be commercially available or can be prepared by methods known to those skilled in the art. The coupling can be accomplished in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and a base, such as potassium carbonate, potassium acetate, or sodium carbonate, in a solvent, such as NMP, DMF, dioxane, or DMSO, or a mixture with water thereof. An intermediate of formula C2 may be deprotected to convert to an intermediate of formula C1 (which may also be a compound of formula I) by reacting with an acid, such as TFA.

[0307] In embodiments wherein R2* is hydrogen, an intermediate of formula C1 may be converted to a compound of formula I, wherein R2is selected from halogen by reacting with a halogenation agent, such as N-chlorosuccinimide, N-bromosuccinimide, or N- iodosuccinimide, in a solvent, such as THF, acetonitrile, DMF, or chloroform.

[0308] In embodiments wherein R2* is hydrogen, an intermediate of formula C2 (an isomeric mixture) may be converted to an intermediate of formula C3 (an isomeric mixture), wherein R2is selected from halogen by reacting with a halogenation agent, such as N- chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide, in a solvent, such as THF, acetonitrile, DMF, or chloroform. An intermediate of formula C3 may be deprotected to convert to a compound of formula I by reacting with an acid such as TFA

[0309] In certain embodiments, whereinone is a double bond,, the preparation of compounds of formula I can be carried out according to Scheme 8.

[0310] Scheme 8

[0311] An intermediates of formula E1 (an isomeric mixture) may be prepared according to Scheme 8 (as an intermediate of formula C2 (an isomeric mixture)). An intermediate of formula E1 (an isomeric mixture) can be converted to an intermediate of formula E2 (an isomeric mixture) by reacting with a hydrogen source, such as molecular hydrogen (H2), in the presence of a catalyst, such as palladium on carbon (Pd / C), in a solvent, such as methanol or ethanol. An intermediate of formula E2, wherein R5 is an acid cleavable group (e.g., BOC), can be converted to a piperidine intermediate of formula E3, or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl. A piperidine intermediate of formula E3, or an acid additional salt thereof, can be converted to a compound of formula I, wherein A isreacting with an electrophilic reagent, such as acetyl chloride, methanesulfonyl chloride, or (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)- yl)sulfonyl)amide, in the presence of a base, such as DIEA, in a solvent, such as DCM.

[0312] An intermediate of formula E1 (an isomeric mixture) can be converted to an intermediate of formula E4, , wherein R5 is an acid cleavable group (e.g., BOC), or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl. An intermediate of formula E4, or an acid addition salt thereof, can be converted to a to a compound of formula I, whereinone is a double bond, by reacting with an electrophilic reagent, such as acetyl chloride, methanesulfonyl chloride, (tert- butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide, in the presence of a base, such as DIEA, in a solvent, such as THF or DCM.

[0313] In certain embodiments, a compound of formula I, for example a compound of formula I prepared according to methods depicted in Schemes 1 to 8, or any combination thereof, can also be an intermediate to one or more additional compounds of formula I. In certain embodiments, such additional compounds of formula I, can be prepared by modifyingR5by methods known to those skilled in the art. The synthetic examples herein provide exemplary modifications of R5.

[0314] In another aspect, also provided are compounds of formula A0, A1, A2, A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, B19, B*, B*-PG, C1, C2, C3, D1, D2, D3, E1, E2, E3, or E4. These compounds are useful as synthetic intermediates for the compounds of formula I, or compounds of a subformula of formula I. EXAMPLES

[0315] The embodiments provided herein will be explained more specifically with reference to the following examples, however, the scope of the embodiments provided herein is not limited to these examples. The isomeric configuration for stereocenters of some enantiomeric compounds described in the Examples has been assigned as R* or S*, but the absolute configuration has not been determined.

[0316] ABBREVIATIONS

[0317] Unless otherwise stated, the following abbreviations have the stated meanings: dba dibenzylideneacetone DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1’-bis(diphenylphosphino)ferrocene dtbpf 1,1’-bis(di-tert-butyl-phosphino)ferrocene eq. equivalent EA ethyl acetate EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl EtOH ethanol FA formic acid HOBt hydroxybenzotriazole HPLC hi h f li id h hLCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide NMP N-methyl-2-pyrrolidone Me methyl MeCN acetonitrile MeOH methanol MOPS 3-(N-morpholino)propanesulfonic acid MS mass spectrometry NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMR nuclear magnetic spectroscopy OAc acetate Pd / C palladium on carbon PE petroleum ether RT room temperature SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride t-Bu tert-butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0318] Generally, crude products were purified by column chromatography or flash chromatography. LCMS analysis or separation was performed using the following methods or methods described for specific examples.

[0319] LCMS METHODS

[0320] Method A

[0321] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.5min; Flow Rate: 1.8ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0322] Method B

[0323] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0324] Method C

[0325] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0326] Method D

[0327] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 2.0ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0328] Method E

[0329] A: H2O (10mmol NH4HCO3), B: MeCN; Gradient: 10-95%B in 1.5min; Flow Rate: 1.8mL / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0330] Method F

[0331] A: H2O (0.05% TFA), B: MeCN (0.05% TFA); Gradient: 5%-95%B in 1.3min, 95%B for 2.9min, 95%-5%B in 0.1min; Flow Rate: 2ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0332] Method G

[0333] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.4min, 95%B for 1.6min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0334] Method H

[0335] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.3.min, 95%B for 1.7min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0336] Method I

[0337] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 10-95%B in 1.5min; Flow Rate: 1.8ml / min; Column: XBridge C18 35μm 46x50mm; Column Temperature: 45°C

[0338] Method J

[0339] A: H2O (0.01% TFA), B: MeCN(0.01% TFA); Gradient: 5%B-95%B in 1min, 95%B for 1min; Flow Rate: 1.6ml / min; Column: Agilent Poroshell 2.7μm, 3.0mmx30mm; Column Temperature: 50°C

[0340] Method K

[0341] A: H2O (0.1% FA), B: MeCN (0.1% FA); Gradient: 10%B for 0.2min, increase to 90%B in 1.3min, 90%B for 1.5min; Flow Rate: 2ml / min; Column: Agilent Poroshell 120 C18, 4.0μm, 4.6x50mm; Column Temperature: 50°C

[0342] Method L:

[0343] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.3min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0344] Method M:

[0345] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 10%-90%B in 1.5min, 95%B for 3min, 95%-10%B in 0.01 min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0346] Method N:

[0347] A: H2O (0.05% FA), B: MeCN (0.035% FA); Gradient: 2%B for 0.2min, 2-98%B in 3.6min, 98%B for 0.5min, 98%-2%B in 0.2min; Flow Rate: 1.0ml / min; Column: Waters ACQUITY UPLC BEH C18, 1.7μm, 2.1x50mm; Column Temperature: 55°C

[0348] Method O:

[0349] A: H2O (0.05% FA), B: MeCN (0.035% FA); Gradient: 2%B for 0.2min, 2-98%B in 8.3min, 98%B for 1min, 98%-2%B in 0.5min; Flow Rate: 0.6ml / min; Column: Waters ACQUITY UPLC BEH C18, 1.7μm, 2.1x50mm; Column Temperature: 55°C

[0350] Method P:

[0351] A: H2O (0.05% FA), B: MeCN (0.045% TFA); Gradient: 2%B for 1min, 2-98%B in 22.5min, 98%B for 4min, 98%-2%B in 2.5min; Flow Rate: 0.6ml / min; Column: Waters ACQUITY UPLC CSHC18, 1.7µm, 2.1x100mm; Column Temperature: 55°C

[0352] SYNTHETIC METHODS

[0353] Table 1: Structure and analytical data of examples

[0354] Example 1: Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate

[0355] Step 1: Preparation of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate

[0356] A mixture of 5-fluoropyridine-2-carboxamidine (100.0 mg, 0.7188 mmol), tert- butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (330.1 mg, 1.078 mmol) and K2CO3 (397.3 mg, 2.875 mmol) was stirred in ethanol (3 mL) at 80°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL) and separated by vacuum filtration. The filtrate was concentrated and purified by flash chromatography (n-heptane / ethyl acetate 100:0 to 50:50) to give tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate (151 mg, purity: 95%, yield: 58%). MS m / z 347.2 [M+H]+.

[0357] Step 2: Preparation of tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate

[0358] A mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate (129.0 mg, 0.3724 mmol) and N-chlorosuccinimide (54.70 mg, 0.4096 mmol) was stirred in dimethylformamide (3 mL) at 70°C for 3 hours. After cooling to room temperature, the solution was purified by flash chromatography (n-heptane / ethyl acetate 100:0 to 50:50) to give 170 mg crude product. Flash chromatography was repeated (n-heptane / ethyl acetate 100:0 to 90:10 to 75:25) to afford the title compound (11 mg, purity: 95%, yield: 7.4%).

[0359] Example 2: 1-[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1- piperidyl]ethanone

[0360] Step 1: Preparation of 2-[4-chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro- pyridine (hydrochloride)

[0361] Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate (10.0 mg, 0.0263 mmol) was dissolved in 1,4-dioxane (2 mL). 4M HCl in 1,4- dioxane (1 mL) was added and the reaction was stirred for 21 hours. The crude product was concentrated in vacuo and used in the next step without further purification.

[0362] Step 2: Preparation of 1-[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1- piperidyl]ethanone

[0363] 2-[4-Chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine hydrochloride (10.0 mg, 0.0315 mmol) was added to dichloromethane (2 mL). Diisopropylethylamine (0.00824 mL, 0.0473 mmol) was added, and the mixture was cooled to 0°C. Acetyl chloride (2.97 mg, 0.0378 mmol) was dissolved in dichloromethane (1 mL) and added via syringe to the mixture within 1 min. The mixture was allowed to reach room temperature and stirred for 16 hours. The mixture was concentrated in vacuo and purified by prep-HPLC to afford the title compound (11.5 mg, purity: 95%, yield: quantitative).

[0364] Example 3: 2-[4-Chloro-5-(1-methylsulfonyl-4-piperidyl)-1H-imidazol-2-yl]-5- fluoro-pyridine

[0365] A mixture of 2-[4-chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine hydrochloride (14.0 mg, 0.0441 mmol), dichloromethane (2 ml), N-ethyl-N-isopropyl-propan- 2-amine (19.2 µl, 0.110 mmol) and methane sulfonyl chloride (6.13 mg, 0.0530 mmol) dissolved in dichloromethane (1 ml) was stirred for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (3.5 mg, purity: 95%, yield: 22%).

[0366] Example 4, Example 5, and Example 6: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2- yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 4), (3S,4S)-4-(4-chloro-2- (5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 5), and (3R*,4S* / 3S*,4R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (Example 6)

[0367] Step 1: Preparation of 5-fluoro-2-(1H-imidazol-2-yl)pyridine

[0368] To a mixture of 5-fluoropicolinaldehyde (100.0 g, 799.35 mmol) and oxalaldehyde (463.91 g,^7.99 mol) in EtOH (2000 mL) was added NH3*H2O (560.28 g,^15.99 mol)^dropwise at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure. The residue was poured into water (2000 mL) and extracted with DCM (1000 mL x 3). The combinedorganic layers were washed with brine (3000 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated to give 5-fluoro-2-(1H-imidazol-2-yl)pyridine (102 g, purity: 98%, yield: 78%) which was used directly in the next step. MS m / z 164.1 [M+H]+.

[0369] Step 2: Preparation of 5-fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)pyridine

[0370] To a solution of 5-fluoro-2-(1H-imidazol-2-yl)pyridine (102 g,^0.63 mol) in THF (2000 mL) was added NaH (60% in oil, 37.55 g, 0.94 mol) in several portions at 0°C under N2 atmosphere.^ The reaction was stirred at 0°C for 1 hour. Then, SEM-Cl (125.4 g, 0.75 mol) was added dropwise maintaining the temperature at 0°C. The reaction mixture was stirred at room temperature for another 6 hours. Then the mixture was quenched with water (2000 mL) and extracted with ethyl acetate (2000 mL x 3). The combined organic layers were washed with brine (2000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 30:70) to give 5- fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (156 g, purity: 85%, yield:^84%). MS m / z 294.0 [M+H]+.

[0371] Step 3: Preparation of a mixture of 2-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine

[0372] 5-Fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (156 g,^0.53 mol) was dissolved in chloroform (1000 mL) under N2 atmosphere. Then, NBS (94.77 g, 0.53 mol) was added in several portions at 0°C. The reaction was stirred at room temperature for 16 hours. Then the solvent was removed. The mixture was poured into water (2000 mL) and extracted with ethyl acetate (1000 mL x 3). The organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 10:90) to give the desired crude product as a mixture of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine (150 g, purity: 85%, yield: 76%). MS m / z 372.0 [M+H]+.

[0373] Step 4: Preparation of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylateand tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3- methyl-3,6-dihydro-2H-pyridine-1-carboxylate

[0374] To a solution of a mixture of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine (65 g, 0.18 mol) in THF (500 mL) and water (50 mL) were added (1-tert-butoxycarbonyl-3-methyl-3,6-dihydro-2H-pyridin-4-yl)boronic acid (55 g, 0.23 mol), potassium carbonate (72.5 g, 0.53 mol) and Pd(dtbpf)Cl2 (17.4 g, 0.027 mol) under nitrogen atmosphere. The reaction was stirred at 80°C for 16 hours. Then the mixture was quenched with water (500 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether 30:70) to afford the subtitle mixture of compounds (54 g,^purity: 85%, yield:^63%). MS m / z 489.2 [M+H]+.

[0375] Step 5: Preparation of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1- carboxylate

[0376] To a solution of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3- methyl-3,6-dihydro-2H-pyridine-1-carboxylate (9 g, 0.02 mol) in methanol (150 mL) was added Pd / C (10%, 0.9 g). The reaction was stirred under hydrogen at room temperature for 72 hours. This reaction was performed in 6 batches in parallel. The mixtures were filtered and washed with methanol (100 mL x 3). The combined filtrates were concentrated and purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to give a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine- 1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate (35 g, purity: 90%, yield:^65%). MS m / z 491.4 [M+H]+.

[0377] Step 6: Preparation of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate

[0378] To a solution of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1- carboxylate (54 g,^0.11 mol) in chloroform (500 mL) was added NCS (17.59 g, 0.13 mol) in several portions at 0°C. The reaction was stirred at 40°C for 16 hours. Then the solvent was removed. The mixture was poured into water (500 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 25:75) to give the desired product as a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (55 g, purity: 85%, yield: 90%). MS m / z 525.3 [M+H]+.

[0379] Step 7: Preparation of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (hydrochloride)

[0380] To a solution of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (44 g, 84 mmol) in THF (40 mL) was added 4 M HCl in 1,4-dioxane (80 mL). The reaction was stirred at room temperature for 16 hours. Then the mixture was concentrated and 4 M HCl in dioxane (80 mL) was added again. The reaction was stirred at room temperature for another 8 hours. LCMS showed the reaction was completed. Then the mixture was concentrated to give 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine hydrochloride (44 g, crude), which was used in the next step without further purification. MS m / z 295.2 [M+H]+.

[0381] Step 8: Preparation of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate

[0382] To a solution of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine hydrochloride (44 g, crude, 84 mmol) in THF (150 mL) were added DIEA (54 g, 0.42 mol) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (27.8 g, 92.4 mmol). The reaction was stirred at room temperature for 36 hours. Then the mixture was quenched with water (200 mL) and extracted with ethyl acetate (400 mL x 3). The organic layers were combined, washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel column chromatography (ethyl acetate / petroleum ether 40:60) to give tert-butyl ((4-(4-chloro-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (25 g, purity: 95%, yield (2 steps): 70%). MS m / z 474.4 [M+H]+.

[0383] Step 9: Preparation of 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide

[0384] To a mixture of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (33 g, 69.8 mmol) in THF (30 mL) was added 4 M HCl in dioxane (60 mL). The reaction was stirred at room temperature for 16 hours. Then the mixture was concentrated, and water (100 mL) was added. The mixture was basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidine-1-sulfonamide (24 g, purity: 95%, yield: 92%). The product is subjected to chiral-HPLC without further purification. MS m / z 374.2 [M+H]+.

[0385] Step 10: Preparation of (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-sulfonamide and (3S,4S)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide and (3R*,4S* / 3S*,4R*)-4-(4-chloro-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide

[0386] The mixture of isomers of 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidine-1-sulfonamide (24.3 g, purity: 95%) was separated by SFC to afford the title compounds.

[0387] Preparative chiral HPLC conditions: Instrument: SFC-200 (Waters); Column: AS 25x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] 75:25; Flow rate: 120 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 8.6 min; Sample solution: 24 g dissolved in 700 ml methanol; Injection volume: 6.0 ml.

[0388] Analytical chiral HPLC conditions: Column: AS-3 4.6*100mm 3µm, Column temperature: 40°C; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] 85:15; Flow rate: 3 ml / min; Back pressure: 2000 psi; Detection wavelength: 254 nm; Run time: 6 min; Injection volume: 5.00 µl.

[0389] (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (9.055 g, yield 38%). Chiral HPLC t=2.53min.

[0390] (3S,4S)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (9.5 g, yield 40%). Chiral HPLC t=4.47min.

[0391] (3R*,4S* / 3S*,4R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (1.1 g, yield 4.6%). Chiral HPLC t=2.04 / 2.11min.

[0392] Example 7: 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methylpiperidine-1-sulfonamide

[0393] Step 1: Preparation of tert-butyl 4-(2-chloroacetyl)-4-methyl-piperidine-1- carboxylate

[0394] To a solution of 1-(tert-butyl) 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (1.0 g, 3.69 mmol) and chloro(iodo)methane (2.59 g, 14.76 mmol) in THF (40 mL), LDA (2 M in THF, 9.23 mL) was added at -78°C.^ After addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (2 mL) in THF (20 mL) was added while keeping the reaction mixture temperature below -65°C. The mixture was stirred for an additional 10 minutes, quenched with water (80 mL) and extracted with ethyl acetate (60 mL x 2). The organic layers were combined, washed with brine (60 mL x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 0:100 to 10:90) to give tert-butyl 4-(2-chloroacetyl)-4-methyl-piperidine-1- carboxylate (864 mg, 85.0% yield). MS m / z 220.1 [M-55]+.

[0395] Step 2: Preparation of tert-butyl 4-(2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4- methylpiperidine-1-carboxylate

[0396] A mixture of 5-fluoropyridine-2-carboxamidine (764 mg, 2.77 mmol), KHCO3 (1.09 g, 10.98 mmol) and tert-butyl 4-(2-chloroacetyl)-4-methyl-piperidine-1-carboxylate (1.51 g, 5.49 mmol) in DMF (20 mL) was stirred at 50°C for 16 h. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product tert-butyl 4-(2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4- methylpiperidine-1-carboxylate (544 mg, 54.5% yield). MS m / z 361.6 [M+H]+.

[0397] Step 3: Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl) -1H-imidazol- 5-yl)-4-methylpiperidine-1-carboxylate

[0398] To a solution of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4-methyl- piperidine-1-carboxylate (544 mg, 1.5 mmol) in MeCN (5 mL) was added NCS (202 mg, 1.8 mmol). The reaction was stirred at room temperature for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer were combined, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether 70:30 to 100:0) to give tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4-methylpiperidine-1-carboxylate (338 mg, 57% yield). MS m / z 395.3 [M+H]+.

[0399] Step 4: Preparation of 2-(4-chloro-5-(4-methylpiperidin-4-yl)-1H-imidazol -2-yl)- 5-fluoropyridine

[0400] To a solution of tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methyl-piperidine-1-carboxylate (96 mg, 0.243 mmol) in DCM (2 mL) was added TFA (1 mL) at 0°C. The reaction was stirred at room temperature for 2 h. The resulting mixture was concentrated to give the crude product 2-(4-chloro-5-(4-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (54 mg, 75% yield). MS m / z 295.3 [M+H]+.

[0401] Step 5: Preparation of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4–methylpiperidin-1-yl)sulfonyl)carbamate

[0402] A solution of [1-(ethoxycarbonylsulfamoyl)-4-pyridylidene]-dimethyl-ammonium (54 mg, 0.18 mmol), 2-[4-chloro-5-(4-methyl-4-piperidyl)-1H-imidazol-2-yl]-5-fluoro- pyridine (66 mg, 0.22 mmol) and TEA (36 mg, 0.36 mmol) in DCM (4 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and^concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether 50:50 to 70:30) to give tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-methylpiperidin-1- yl)sulfonyl)carbamate (44 mg, 51.7% yield). MS m / z 474.1 [M+H]+.

[0403] Step 6: Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methylpiperidine-1-sulfonamide

[0404] To a solution of tert-butyl N-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-4-methyl-1- piperidyl]sulfonyl]carbamate (44 mg, 0.093 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0°C. The reaction was stirred at room temperature for 1 h. The resulting mixture was concentrated and purified by prep-HPLC to afford title compound (4.2 mg, 12.1% yield).

[0405] Example 8: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2- hydroxyethyl)-3-methylpiperidine-1-sulfonamide

[0406] Step 1: Resolution of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine: Preparation of 2-(4-chloro-5-((3S*,4R* / 3R*,4S*)-3-methylpiperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine, 2-(4-chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol- 2-yl)-5-fluoropyridine and 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)- 5-fluoropyridine

[0407] The mixture of isomers of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (1.6 g) was separated by SFC to afford the title compounds.

[0408] Preparative chiral HPLC conditions: Instrument: Instrument: SFC-150 (Waters); Column: AS 20x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / EtOH (0.5% NH3 (7M in MeOH) 80:20; Flow rate: 100 ml / min; Back pressure: 100 bar;Detection wavelength: 214 nm; Cycle time: 4.3 min; Sample solution: 1600 mg dissolved in 100 ml methanol; Injection volume: 2.0 ml.

[0409] Analytical chiral HPLC conditions: Column: AS-H 4.6*100mm 5µm; Column temperature: 40°C; Mobile phase: CO2 / EtOH (0.5% NH3 (7M in MeOH) 90:10; Flow rate: 3 ml / min; Back pressure: 2000 psi; Detection wavelength: 214 nm; Run time: 7 min; Injection volume: 5.00 µl.

[0410] 2-(4-Chloro-5-((3S*,4R* / 3R*,4S*)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (500 mg, impure). MS (method A) 295.1 (M+H)+, t=1.48min. 1H NMR (500 MHz, DMSO-d6) δ (selected signals) 8.61 – 8.54 (m, 1H), 8.03 (m, 1H), 7.85 – 7.76 (m, 1H), 3.31 – 3.22 (m, 2H), 3.20 – 2.73 (m, 2H), 2.48 – 2.26 (m, 1H), 2.19 – 1.90 (m, 2H), 1.73 – 1.45 (m, 1H), 0.99 – 0.54 (m, 3H) ppm. Chiral HPLC t=1.32min.

[0411] 2-(4-Chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (400 mg, purity: 99%, yield 25%). MS (method A) m / z 295.1 (M+H)+, t=1.41min. 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.5, 4.5 Hz, 1H), 7.82 (td, J = 9.0, 3.0 Hz, 1H), 3.03 (d, J = 13.0 Hz, 2H), 2.77 (d, J = 2.0 Hz, 2H), 2.57 – 2.51 (m, 1H), 2.39 – 2.23 (m, 1H), 1.94 – 1.84 (m, 1H), 1.40 (d, J = 11.0 Hz, 1H), 0.86 (d, J = 7.0 Hz, 3H) ppm. Chiral HPLC t=2.74min.

[0412] 2-(4-Chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (420 mg, purity: 100%, yield 26%). MS (method A) m / z 295.2 (M+H)+, t=1.41min. 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.5, 4.5 Hz, 1H), 7.82 (td, J = 9.0, 3.0 Hz, 1H), 3.03 (d, J = 13.0 Hz, 2H), 2.77 (d, J = 2.0 Hz, 2H), 2.56 – 2.51 (m, 1H), 2.38 – 2.23 (m, 1H), 1.90 (s, 1H), 1.39 (d, J = 11.0 Hz, 1H), 0.86 (d, J = 7.0 Hz, 3H) ppm. Chiral HPLC t=3.64min.

[0413] Step 2: Preparation of 3-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)oxazolidin-2-one

[0414] To a solution of sulfurisocyanatidic chloride (48 mg, 0.34 mmol) in^dichloromethane (2 mL) was added 2-bromoethan-1-ol (43 mg, 0.34 mmol) under N2. The solution was cooled to 0°C^and stirred for 1 hour. Then 2-(4-chloro-5-((3R,4R)-3- methylpiperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (100 mg, 0.34 mmol) and triethylamine (103 mg, 1.02 mmol) were added. The mixture was stirred at room temperaturefor 4 h. The reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to afford the title compound (110 mg, yield: 73%). MS m / z 444.1 [M+H]+.

[0415] Step 3: Preparation of (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-N-(2-hydroxyethyl)-3-methylpiperidine-1-sulfonamide

[0416] To a solution of 3-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)oxazolidin-2-one (110 mg, 0.25 mmol) in ethanol (2 mL) was added a solution of sodium hydroxide (12 mg,^0.3 mmol ) in water (2 mL). The reaction was^stirred at room temperature^for^2 h. Then the mixture was concentrated under reduced pressure and then water (20 mL) was added. The resulting mixture was extracted with ethyl acetate (25 mL x 3), washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to afford the title compound (68.5 mg, 0.16 mmol, yield: 66%).

[0417] Example 9: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-carboxamide

[0418] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in^dichloromethane (2 mL) was added DIEA (70 mg, 0.54 mmol) at 0°C and stirred for 10 min. Then trimethylsilylisocyanate (31 mg, 0.41 mmol) was added slowly. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (57.3 mg, 0.17 mmol, yield: 62%).

[0419] Example 10: 2-(4-Chloro-5-((3R,4R)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine

[0420] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in^dichloromethane (2 mL) was added DIEA (176mg, 1.36 mmol) at 0°C and stirred for 10 min. Then methanesulfonyl chloride (47 mg, 0.41 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (45.3 mg, 0.12 mmol, yield: 45%).

[0421] Example 11: 1-((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)ethan-1-one

[0422] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in^dichloromethane (2 mL) was added DIEA (105 mg, 0.82 mmol) at 0°C and stirred for 10 min. And then acetyl chloride (25 mg, 0.33 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (50.6 mg, 0.15 mmol, yield: 56%).

[0423] Example 12 and Example 13: (3S*,4S*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 12) and (3R*,4R*)-4-(4-ethyl-2- (5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 13)

[0424] Step 1: Preparation of 5-fluoropicolinimidamide

[0425] To a solution of 4-fluoro-benzonitrile (20 g, 164 mmol) in dry THF (300 mL) was added LiHMDS (1M in THF, 328 mL, 328 mmol) slowly at -78°C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride (300 mL) and extracted with dichloromethane (300 mL x 3). The organic layers were combined, washed with brine (200 mL x 3), dried over anhydrous sodium sulfate and concentrated to give 5-fluoropicolinimidamide (8 g, 35% yield). MS m / z 140 [M+H]+.

[0426] Step 2: Preparation of 2-(4-ethyl-1H-imidazol-2-yl)-5-fluoropyridine

[0427] To a solution of 5-fluoropicolinimidamide (5 g, 36 mmol) in EtOH (30 ml) was added 1-bromobutan-2-one (5.6 g, 36 mmol) and K2CO3 (4.9 g, 36 mmol). The reaction mixture was stirred at 80°C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give 2-(4-ethyl-1H-imidazol-2-yl)-5- fluoropyridine (3 g, crude), which was used for the next step without further purification. MS m / z 192 [M+H]+.

[0428] Step 3: Preparation of 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine

[0429] To a solution of 2-(4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (3 g, 15 mmol) in MeCN (100 mL) was added N-bromosuccinimide (3.2 g, 18 mmol). The reaction was stirred at room temperature for 16 h. The resulting mixture was diluted with EA (200 mL), washed with brine (200 mL x 3), dried over anhydrous sodium sulfate and concentrated. The crude was purified by column chromatography on silica gel (ethyl acetate / petroleum ether 20:80) to give 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (3.2 g, 75.5% yield). MS m / z 270 [M+H]+.

[0430] Step 4: Preparation of a mixture of 2-[[5-bromo-4-ethyl-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-5-ethyl-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0431] To a solution of 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (1 g, 3.7 mmol) in THF (dry, 30 mL) was added NaH (133 mg, 5.5 mmol) and 2-(chloromethoxy)ethyl- trimethyl-silane (926 mg, 5.5 mmol) at 0°C. The reaction was stirred at room temperature for 4 h. The mixture was diluted with EA (100 mL), washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated. The crude was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 5) to afford the subtitle compounds (700 mg, 47.2% yield). MS m / z 400 [M+H]+.

[0432] Step 5: Preparation of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1- carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate

[0433] To a solution of a mixture of 2-[[5-bromo-4-ethyl-2-(5-fluoro-2-pyridyl)imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-5-ethyl-2-(5-fluoro-2-pyridyl)imidazol- 1-yl]methoxy]ethyl-trimethyl-silane (700 mg, 1.7 mmol) in dioxane (30 mL) and water (3 mL) were added (1-(tert-butoxycarbonyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (750 mg, 2.5 mmol), potassium carbonate (470 mg, 3.4 mmol) and Pd(tbdpf)Cl2 (115 mg, 0.17 mmol) under nitrogen atmosphere. The reaction was stirred at 70°C for 4 hours. Then the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 20:80) to afford the subtitle compounds (741 mg, 1.43 mmol, yield:^85%). MS m / z 517 [M+H]+.

[0434] Step 6: Preparation of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate

[0435] To a solution of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (741 mg, 1.43 mmol) in methanol (10 mL) was added Pd / C (10%, 100 mg). The reaction was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and the solid washed with methanol (10 mL x 3). The combined filtrates were concentrated and the residue purified by flash chromatography (ethyl acetate / petroleum ether 30:70) to give a mixture of tert-butyl 4-[5- ethyl-2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate (703 mg, 1.35 mmol, 95% yield). MS m / z 519 [M+H]+.

[0436] Step 7: Preparation of 2-(4-ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine

[0437] To a solution of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (800 mg, 1.54 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. Then the mixture was concentrated to give the product 2-(4- ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (400 mg, 1.38 mmol, crude), which was used in the next step without further purification. MS m / z 289 [M+H]+.

[0438] Step 8: Preparation of tert-butyl ((4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate

[0439] To a solution of 2-(4-ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (270 mg, 0.93 mmol) in DCM (10 mL) were added DIEA (232 mg, 1.86 mmol) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (308 mg, 0.99 mmol). The reaction was stirred at room temperature for 4 hours. Then the mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel column chromatography (ethyl acetate / petroleum ether 50:50) to give tert-butyl ((4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (340 mg, 0.72 mmol, 78% yield). MS m / z 468 [M+H]+.

[0440] Step 9: Preparation of 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-piperidine-1-sulfonamide

[0441] To a solution of tert-butyl N-[[4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]carbamate (370 mg, 1 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in dioxane (5 mL). The reaction was stirred at room temperature for 2 hours. Then the mixture was concentrated, and water (40 mL) was added. The mixture was basified with saturated K2CO3 solution to pH = 9 and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-piperidine-1-sulfonamide (250 mg, 0.68 mmol, 68% yield).

[0442] Step 10: Preparation of (3R*,4R*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide and (3S*,4S*)-4-(4-ethyl-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide

[0443] The isomers of 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-sulfonamide were separated by chiral SFC to afford the title compounds.

[0444] Preparative chiral separation conditions: Instrument: SFC-150 (Waters); Column: AS 25x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH) 70:30; Flow rate: 100ml / min; Back pressure: 100bar; Detection wavelength: 214nm; Cycle time: 4.5min; Sample solution: 270mg dissolved in 25ml methanol; Injection volume: 1ml.

[0445] Analytical chiral separation conditions: Column: AS3 4.6x100mm, 3μm; Column temperature: 40°C; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH) 80:20; Flow rate: 3ml / min; Back pressure: 2000psi; Detection wavelength: 214nm; Run time: 5min; Injection volume: 5µl.

[0446] (3R*,4R*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (70 mg, 28% yield). Chiral HPLC 1.54min.

[0447] (3S*,4S*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (90 mg, 36% yield). Chiral HPLC 1.23min.

[0448] Example 14: Methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidin-1-yl)sulfonyl)glycinate

[0449] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (150 mg, 0.51 mmol) in^dichloromethane (3 mL) was added triethylamine (155 mg, 1.53 mmol) under N2. And then methyl (chlorosulfonyl)glycinate (954 mg, 5.10 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to afford the title compound (120 mg, 0.27 mmol, yield: 53%).

[0450] Example 15: (((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)glycine

[0451] To a solution of methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)glycinate (90 mg, 0.20 mmol) in THF (2 mL) was added a solution of lithium hydroxide (15 mg,^0.6 mmol) in water (2 mL). The reaction was^stirred at room temperature^for^2 h. The mixture was extracted with ethyl acetate (15 mL x 3), washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to afford the title compound (74 mg, 0.17 mmol, yield: 85%).

[0452] Example 16: 2-(4-Chloro-5-((3S,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine

[0453] To a solution of 2-(4-chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (100 mg, 0.34 mmol) in^dichloromethane (2 mL) was added DIEA (132 mg, 1.02 mmol) at 0°C and stirred for 10 min. And then methanesulfonyl chloride (58 mg, 0.51 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (19.6 mg, 0.05 mmol, yield: 15%).

[0454] Example 17: 2-(4-Chloro-5-((3R*,4S* / 3S*,4R*)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine

[0455] To a solution of 2-(4-chloro-5-((3R*,4S* / 3S*,4R*)-3-methylpiperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (200 mg, 0.68 mmol) in^THF (4 mL) was added DIEA (263 mg, 2.04 mmol) at 0°C and stirred for 10 min. And then methanesulfonyl chloride (116 mg, 1.02 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate,filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (16.3 mg, 0.04 mmol, yield: 6%).

[0456] Example 18: 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide

[0457] Step 1: Preparation of methyl-1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate

[0458] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (190 mg, 0.65 mmol) in^THF (2 mL) was added DIEA (167 mg, 1.3 mmol) at 0°C and stirred for 10 min. And then methyl-1-(chlorosulfonyl)azetidine-3- carboxylate (96 mg, 0.78 mmol) was added slowly. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 30:70) to afford the subtitle compound (180 mg, 0.38 mmol, yield: 59%). MS m / z 472.1 [M+H]+.

[0459] Step 2: Preparation of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid

[0460] To a solution of methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate (180 mg, 0.38 mmol) in MeOH (2 mL) was added a solution of sodium hydroxide (76 mg,^1.91 mmol ) in water (2 mL). The reaction was^stirred at room temperature^for^16 h. Then the mixture was diluted with water (20 mL), acidified with 1 M HCl solution to pH 4, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuum to afford the subtitle compound (130 mg, 0.28 mmol, yield: 74%). MS m / z 458.0 [M+H]+.

[0461] Step 3: Preparation of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide

[0462] To a solution of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid (100 mg, 0.22 mmol) in DCM(2 mL) were added DIEA (225 mg, 1.75 mmol), NH4Cl (59 mg, 1.09 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 hours. Then the crude product was purified by prep-HPLC to afford the title compound (83.6 mg, 0.18 mmol, yield: 84%).

[0463] Example 19: (S*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine

[0464] Step 1: Preparation of 5-fluoro-2-(1H-imidazol-2-yl)pyridine

[0465] To a mixture of 5-fluoropicolinaldehyde (100.0 g, 799.35 mmol) and oxalaldehyde (463.91 g,^7.99 mol) in EtOH (2000 mL) was added NH3*H2O (560.28 g,^15.99 mol)^dropwise at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure. The residue was poured into water (2000 mL) and extracted with DCM (1000 mL x 3). The combined organic layers were washed with brine (3000 mL x 2), dried with Na2SO4, filtered and concentrated to give the crude product 5-fluoro-2-(1H-imidazol-2-yl)pyridine (100 g) which was used directly in the next step. MS m / z 164.1 (M+H)+.

[0466] Step 2: Preparation of 2-(4,5-diiodo-1H-imidazol-2-yl)-5-fluoropyridine

[0467] 5-Fluoro-2-(1H-imidazol-2-yl)pyridine (100 g, 612.91 mmol) was dissolved acetonitrile (1000 ml) under N2 atmosphere. Then, NIS (303.4 g, 1.35 mol) was added in several portions at 0°C. The reaction mixture was stirred at room temperature for 6 hours. Then the solvent was removed. The residue was poured into water (2000 mL) and extracted with ethyl acetate (1000 mL x 3). The organic layers were washed with brine (1000 mL x 3), dried with Na2SO4, filtered and concentrated to afford the crude subtitle compound (219 g) which was used directly in the next step. MS m / z 415.8 (M+H)+.

[0468] Step 3: Preparation of 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine

[0469] To a solution of 2-(4,5-diiodo-1H-imidazol-2-yl)-5-fluoropyridine (219 g, 527.78 mmol) in DMF (2000 mL) and water (1000 mL) was added Na2SO3 (399 g,^3.166 mol) in several portions. The reaction was stirred at^120°C for 16 hours. Then the reaction mixture was poured into water (5000 mL) and extracted with ethyl acetate (3000 mL x 3). The combined organic layers were washed with brine (5000 mL x 3), dried with Na2SO4, filteredand concentrated to give the crude product 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine (130 g) which was used directly in the next step. MS m / z 289.9 (M+H)+.

[0470] Step 4: Preparation of a mixture of 5-fluoro-2-(4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine and 5-fluoro-2-(5-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine

[0471] To a solution of 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine (130 g,^0.45 mol) in THF (2000 mL) was added NaH (26.99 g, 0.675 mol, 60%) in several portions at 0°C under N2 atmosphere.^The resulting mixture was stirred at 0°C for 1 hour. Then, SEM-Cl (90 g, 0.54 mol) was added dropwise maintaining the temperature at 0°C. The reaction was stirred at room temperature for another 6 hours. The reaction mixture was quenched by adding water (2000 mL) slowly and extracted with ethyl acetate (2000 mL x 3). The combined organic layers were washed with brine (5000 mL x 2), dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (Biotage Flash, ethyl acetate / petroleum ether 25:75) to afford the subtitle compounds (170 g, 0.405 mol, yield:^50.7% in 4 steps). MS m / z 420.0 (M+H)+.

[0472] Step 5: Preparation of a mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine

[0473] To a solution of a mixture of 5-fluoro-2-(4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine and 5-fluoro-2-(5-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (10 g,^23.9 mmol) in THF (100 mL) was added NCS (3.81 g, 28.6 mmol) in several portions. The reaction mixture was stirred at 40°C for 16 h. The mixture was poured into water (150 mL) and extracted with EA (150 mL x 3). The organic layers were washed with brine (150 mL x 2), dried with Na2SO4 and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 20:80) to give the desired mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (5.6 g, 12.4 mmol, yield: 52%). MS m / z 454.0 [M+H]+.

[0474] Step 6: Preparation of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1- carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate

[0475] To a solution of a mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (1 g, 2.2 mmol) in THF (10 mL)^ were added (1-(tert-butoxycarbonyl)-3-methyl-1,2,3,6-tetrahydropyridin-4- yl)boronic acid (798 mg, 3.3 mmol) and potassium carbonate (914 mg, 6.6 mmol) in water (2 mL). And then Pd(dtbpf)Cl2 (285 mg, 0.44 mmol) was added under N2 atmosphere. The reaction was stirred at 80°C for 16 h. The reaction mixture was quenched with adding water (80 mL) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 30:70) to give a mixture of tert-butyl 4-[5- chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6- dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 0.96 mmol, yield:^43 %). MS m / z 523.2 [M+H]+.

[0476] Step 7: Preparation of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine

[0477] A mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 0.96 mmol) and TFA (4 mL) was stirred at room temperature for 2 hours. Then the mixture was concentrated, diluted with water (20 mL), basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(4-chloro-5-(3-methyl- 1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (200 mg, 0.68 mmol,yield: 72%). The crude product is subjected to chiral HPLC without further purification. MS m / z 293.1 [M+H]+.

[0478] Step 8: Preparation of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4- yl)-1H-imidazol-2-yl)-5-fluoropyridine and (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine

[0479] The enantiomeric mixture 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine (270 mg) was separated by chiral HPLC to give (S*)-2-(4- chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (130 mg) and (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (125 mg).

[0480] Preparative chiral HPLC conditions: Instrument: SFC-150 (Waters); Column: AD 25x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2 / MeOH (0.2% NH3(7M in MeOH) 75:25; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.0 min; Sample solution: 300 mg dissolved in 35 ml methanol; Injection volume: 1.0 ml.

[0481] Analytical chiral HPLC conditions: Column: AD-H 4.6x100µm, 5μm; Column temperature: 40°C; Mobile phase: CO2 / MeOH (0.2% NH3(7M in MeOH) 75:25; Flow rate: 3ml / min; Back pressure: 2000psi; Detection wavelength: 214 nm; Run time: 4.0 min; Injection volume: 7.00 µl. (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine. Chiral HPLC 0.87 min. (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine. Chiral HPLC 1.12min.

[0482] Step 9: Preparation of (S*)-2-(4-chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine

[0483] To a solution of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (65 mg, 0.22 mmol) in DCM (2 mL) was added DIEA (86 mg, 0.67 mmol) at 0°C. Then methanesulfonyl chloride (30 mg, 0.27 mmol) was added dropwise. The reaction was stirred at room temperature for 3 hours. Then the mixture was quenched with water (10 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered andconcentrated. The crude product was purified by prep-HPLC to afford the title compound (36.5 mg, 0.10 mmol, yield: 44%).

[0484] Example 20: (R*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine

[0485] To a solution of (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (60 mg, 0.21 mmol) in DCM (2 mL) was added DIEA (80 mg, 0.62 mmol) at 0°C. Then methanesulfonyl chloride (28 mg, 0.25 mmol) was added slowly. The reaction was stirred at room temperature for 3 hours. Then the mixture was quenched with water (10 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (28.1 mg, 0.08 mmol, yield: 37%).

[0486] Example 21: (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonamide

[0487] Step 1: Preparation of tert-butyl (S*)-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate

[0488] To a solution of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (65 mg, 0.22 mmol) in DCM (2 mL) were ad...

Claims

CLAIMS 1. A compound of formula I, wherein: A is selected from ,each is a single or a double bond, provided two adjacent are not both double bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6haloalkyl; each instance of R3is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R4is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6 haloalkyl;R4Pis selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, - OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, - NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, - S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3arylalkyl, monocyclic heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(arylene)R13, heterocyclyl, or -(heterocyclylene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, - OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, or -NR9S(=O)2NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or more R13;each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or more R13; each instance of R13is independently selected from halogen, C1-C4alkyl, C1-C4haloalkyl, -OH, -O(C1-C4alkyl), -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4alkyl), -NHC(=O)N(C1-C4alkyl)(C1-C4alkyl), -N(C1-C4alkyl)C(=O)(C1- C4alkyl), -N(C1-C4alkyl)C(=O)OH, -N(C1-C4alkyl)C(=O)O(C1-C4alkyl), -N(C1-C4alkyl)C(=O)NH2, -N(C1-C4alkyl)C(=O)NH(C1-C4alkyl), -N(C1-C4alkyl)C(=O)N(C1-C4alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a heterocyclyl ring; X1is halogen; m is 0 or 1; n is 1 or 2; each p is independently 1, 2, or 3; and each q is independently 1, 2, or 3;wherein when, R4and R5may be taken together with the carbons connecting them to form a 5- or 6-membered heterocyclyl ring; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,.

2. The compound of formula I according to claim 1, wherein: A is selected fromR1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3haloalkyl; R2is selected from halogen, -OR11, -NR11R12, C1-C4alkyl, C1-C4heteroalkyl, and C1- C3haloalkyl; each instance of R3 is independently selected from halogen, -OR11, -NR11R12, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3haloalkyl; R4Pis selected from halogen, -OR11, -NR11R12, C1-C4alkyl, C1-C4heteroalkyl, and C1- C3haloalkyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -SR7, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O- )R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR )NR R S(=O)R S(=O) R S(=O) NR R S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(phenylene)R13, 4- to 6- membered heterocyclyl, or -(4- to 6-membered heterocyclene)R13; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, C3- C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, C1-C4acyl, and C1-C4sulfonyl provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4alkyl)(C1-C4alkyl), -OC(=O)(C1-C4alkyl), -OC(=O)OH, -OC(=O)O(C1-C4alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4alkyl), -OC(=O)N(C1-C4alkyl)(C1-C4alkyl), - NHC(=O)(C1-C4alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1-C4alkyl), -N(C1-C4alkyl)C(=O)OH, -N(C1-C4alkyl)C(=O)O(C1-C4alkyl), -N(C1-C4alkyl)C(=O)NH2, -N(C1-C4alkyl)C(=O)NH(C1-C4alkyl), -N(C1-C4alkyl)C(=O)N(C1-C4alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4- to 6-membered heterocyclyl ring; m is 0 or 1; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of formula I according to claim 1 or 2, wherein: A is selected fromR1is selected from halogen; R2is selected from halogen and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R4 is selected from hydrogen and C C alkyl;R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, - NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pC(=O)OR11, -(CH2)p(phenylene)R13, or –(4- to 6- membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6-membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1- C4heteroalkyl, C3-C6cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4acyl, and C1-C4sulfonyl provided R11is not C1-C4sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -OC(=O)(C1-C4alkyl), -OC(=O)O(C1-C4alkyl), -(CH2)qOH, and - S(=O)2(C1-C4alkyl), and wherein two R13groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4-membered heterocyclyl ring;m is 0; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

4. The compound of formula I according to any one of claims 1-3, wherein: A is selected fromR2is selected from chloro, bromo, methyl, and ethyl; R4is selected from fluoro, chloro, and methyl; R4Pis selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)OR11, -(CH2)C(=O)OR11, -(CH2)(phenylene)R13, or –(4- to 6-membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, 4 to 6-membered heterocyclyl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, or -C(=O)NR11R12,; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, C3- C6 cycloalkyl, 4- to 6- membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33- to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4acyl, and C1-C4sulfonyl provided R11is not C1-C4sulfonyl when R11is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, -C(=O)OtBu, -OC(=O)Me, -OC(=O)OMe, -OC(=O)OEt, -(CH2)OH, and -S(=O)2(Me), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form:; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-A,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

6. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-B ,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-D ,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

8. The compound of formula I according to any one of claims 1-4, wherein the compound is ofI-G1, wherein: L1 is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; and j is 0, 1, or 2; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

9. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-HI-H,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

10. The compound of formula I according to any one of claims 1-4, wherein the compound is of any one of formulas I-J1 to I-J5,wherein: z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, - S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, - (CH2)p(arylene)R13, heterocyclyl, or -(heterocyclene)R13; each instance of E1is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

11. The compound of formula I according to any one of claims 1-4, wherein the compound is of any one of formulas I-K1 to I-K8wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

12. The compound of formula I according to any one of claims 1 to 11, wherein R1 is selected from halogen and C1-C4 alkyl; R2 is selected from halogen and C1-C4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

13. The compound of formula I according to any one of claims 1 to 12, wherein R1 is fluoro; R2 is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

14. The compound of formula I according to any one of claims 1 to 6, wherein R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

15. The compound of formula I according to any one of claims 1 to 4, 7, and 9-13, wherein R4Pis selected from hydrogen and C1-C4alkyl;or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

16. The compound of formula I according to any one of claims 1 to 15, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

17. The compound of formula I according to claim 16, wherein R5 is -S(=O)2R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

18. The compound of formula I according to claim 16, wherein R5is selected from , ,, , ,or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

19. A compound selected from: Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate;1-[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1-piperidyl]ethenone; 2-[4-Chloro-5-(1-methylsulfonyl-4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine; (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-sulfonamide; (3S,4S)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1- sulfonamide; (3R*,4S* / 3S*,4R*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4-methylpiperidine-1- sulfonamide; (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2-hydroxyethyl)- 3-methylpiperidine-1-sulfonamide; (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-carboxamide; 2-(4-Chloro-5-((3R,4R)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine; 1-((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)ethan-1-one; (3S*,4S*)-4-(4-Ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-sulfonamide; (3R*,4R*)-4-(4-Ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-sulfonamide; Methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)glycinate; (((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidin- 1-yl)sulfonyl)glycine; 2-(4-Chloro-5-((3S,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine; 2-(4-Chloro-5-((3R*,4S* / 3S*,4R*)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine;1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide; (S*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine; (R*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine; (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonamide; (R*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonamide; 2-(5-((3R,4R)-1-((1H-Pyrazol-4-yl)sulfonyl)-3-methylpiperidin-4-yl)-4-chloro-1H- imidazol-2-yl)-5-fluoropyridine; Methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate; 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid; 2-(4-Bromo-5-(2,3-difluorophenyl)-1H-imidazol-2-yl)-5-fluoropyridine; 2-(4-Bromo-5-(2-chlorophenyl)-1H-imidazol-2-yl)-5-fluoropyridine; 2-[4-Chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; 2-[4-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; 2-[4-Chloro-5-(2-chloro-4-(methylsulfonimidoyl)phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; Methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzoate; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzoic acid; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzenesulfonamide; 2-[[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]acetic acid;3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-(2- hydroxyethyl)benzenesulfonamide; 2-[5-(2-Chloro-4-methylsulfonyl-phenyl)-4-methyl-1H-imidazol-2-yl]-5-fluoro- pyridine; Methyl 1-((3-chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)azetidine-3-carboxylate; 1-((3-Chloro-4-(4-chloro-2-(5-fluoro-pyridin-2-yl)-1H-imidazol-5-yl)-phenyl) sulfonyl)azetidine-3-carboxylic acid; 1-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)azetidine-3-carboxamide; Methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)benzoate; 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)benzoic acid; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2,3-dihydro-1,2-benzothiazole 1,1-dioxide; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2-methylbenzenesulfonamide; 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)benzamide; 2-(4-Chloro-5-(2-fluoro-6-methylphenyl)-1H-imidazol-2-yl)-5-fluoropyridine; Methyl 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzoate; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2-methylbenzoic acid; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2-methylbenzamide; 2-(4-Chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1H-imidazol-2-yl)-5- fluoropyridine; 2-[4-Chloro-5-(2-fluoro-6-methyl-4-methylsulfonyl-phenyl)-1H-imidazol-2-yl]-5- fluoro-pyridine; 3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropan-1-ol; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzenesulfonamide;3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropanamide; 4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylbenzoic acid; Methyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylbenzoate; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-benzamide; N-(2-Amino-2-oxo-ethyl)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-benzamide; 2-(4-Chloro-5-(2-methyl-4-(methylthio)phenyl)-1H-imidazol-2-yl)-5-fluoropyridine; N-(2-Amino-2-oxo-ethyl)-3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzamide; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzamide; 2-[4-Chloro-5-(2-methyl-4-methylsulfonyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; 2-[4-Chloro-5-(2-methyl-4-methylsulfinyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; Tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxylate; Tert-butyl (R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxylate; (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,N,3-trimethyl- piperidine-1-carboxamide; Methyl (3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-carboxylate; [2-(Dimethylamino)-2-oxo-ethyl] (3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-piperidine-1-carboxylate; Methyl 3-[[(3S*)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonyl]propanoate; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-pyridine;2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-1-oxido-pyridin-1-ium; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-oxidopyridin-1-ium-3-yl)sulfonyl-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[5-[(3R,4R)-1-(Azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4-chloro-1H-imidazol- 2-yl]-5-fluoro-pyridine; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]azetidin-1-yl]ethanone; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]azetidine-1-carboxamide; Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]butanoate; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2,2-dimethyl-propanoate; Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate; 2-[5-[(3R,4R)-1-(Azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]-4-chloro-1H- imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2-methyl-pyridine; 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethoxy]ethanol; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]butanoic acid; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2,2-dimethyl-propanoic acid; 2-[4-Chloro-5-[(3R,4R)-1-[(6-methoxy-3-pyridyl)sulfonyl]-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]butanamide;3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2,2-dimethyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]azetidine-1-carboxamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1H-pyridin-2-one; 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethoxy]acetic acid; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydrofuran-3-ylsulfonyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(oxetan-3-ylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-1-[(2-methoxy-4-pyridyl)sulfonyl]-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1H-pyridin-2-one; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoic acid; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1); 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 2); 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-methyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 1);3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 2); (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,N-bis(2-hydroxyethyl)- 3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide; (3R,4R)-1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonyl]pyrrolidine-3,4-diol; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-N-(1H-tetrazol- 5-ylmethyl)-3,6-dihydro-2H-pyridine-1-sulfonamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propyl acetate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propan-1-ol; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-methylsulfonyl-propanamide; (5R)-5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]imidazolidine-2,4-dione; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[2-hydroxy-1- (hydroxymethyl)ethyl]-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide; 4-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]piperazin-2-one; (2S)-2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonylamino]propenamide; 1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]azetidin-3-ol; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-N-(2- oxopyrrolidin-3-yl)-3,6-dihydro-2H-pyridine-1-sulfonamide; 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic;5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2-methoxy-pyrimidine acid; Methyl 2-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetate; 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl-methyl-amino]acetamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-methyl-pyridin-2-one; 2-[4-Chloro-5-[(3R,4R)-1-[2-[2-[(4-methoxyphenyl)methyl]tetrazol-5- yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrazol-1-yl]acetic acid; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-ol; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2H-tetrazol-5-yl)ethylsulfonyl]-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; Methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonyl]propanoate; 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridin-1-yl]sulfonyl]propenamide; 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridin-1-yl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one; 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridin-1-yl]sulfonyl]-N-cyclopropyl-propanamide; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-N-[(5-methyl- 1,3,4-oxadiazol-2-yl)methyl]piperidine-1-sulfonamide; [1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]azetidin-3-yl]methanol;N-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]piperidine-3-carboxamide; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[(2S)-2-hydroxypropyl]- 3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide; 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonylamino]-N,N-dimethyl-acetamide; 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylamino]-N,N-dimethyl-acetamide; Tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl]-3- methylpiperidine-1-carboxylate; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridine-1-sulfonamide; 2-Chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- 1-piperidyl]sulfonyl]pyrimidine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylpyrazol-4-yl)sulfonyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,3-dimethyl- piperidine-1-carboxamide; 1-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]azetidin-3-ol; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]ethanol; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1-methyltetrazol-5-yl)ethylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridin-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-cyclopropyl-pyrimidin-2-amine;4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-methyl-pyrrolidin-2-one; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-methyl-pyrimidin-2-amine; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N,N-bis(trideuteriomethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-hydroxy-2-methyl-propyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-cyclopropyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3R)-3-hydroxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3S)-3-hydroxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-methoxyazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-hydroxy-3-methyl-azetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(4-hydroxy-1-piperidyl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-methoxyethyl)propenamide; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2-methyltetrazol-5-yl)ethylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate; 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]acetamide; Tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate;2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonylazetidin-3-yl)methylsulfonyl]- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylazetidin-3-yl)sulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]thiazol-2-amine; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]azetidin-1-yl]ethenone; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(trideuteriomethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(oxetan-3-yl)propenamide; 2-[4-Chloro-5-[(3R,4R)-1-(1H-imidazol-4-ylsulfonyl)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-ethyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(4-hydroxy-4-methyl-1-piperidyl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-morpholino-propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(cyclopropylmethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-pyrrolidin-1-yl-propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2,2,2-trifluoroethyl)propenamide; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]azetidine-1-carboxylate; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]azetidine-1-carboxylate;N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]acetamide; N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]methanesulfonamide; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]furan-2-carboxylate; 5-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]-3-methyl-1,2,4-oxadiazole; Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethyl]carbamate; 2-[4-Chloro-5-[(3R,4R)-1-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethylsulfonyl]- 3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethanamine; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(oxetan-3-ylmethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(4-methoxy-1-piperidyl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-tetrahydropyran-4-yl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[(3S)-tetrahydropyran-3-yl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-1-one;2-[4-Chloro-5-[(3R,4R)-1-(2-methoxyethylsulfonyl)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydropyran-4-ylsulfonyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(tetrahydrofuran-3-ylmethylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-yl]acetamide; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-4-methyl-thiazol-2-yl]acetamide; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridine-2-carboxylate; Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxylate; Tert-butyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]piperidine-1-carboxylate; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1H-triazol-4-yl)ethylsulfonyl]-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4-piperidyl]-1H-imidazol- 2-yl]-5-fluoro-pyridine; Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethylsulfamoyl]carbamate; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-4-methyl-thiazol-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridine-2-carboxylic acid;3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]-5-methyl-1,2,4-oxadiazole; 1-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-piperidyl]ethenone; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonyl-4-piperidyl)sulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(sulfamoylamino)ethylsulfonyl]-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylpyrrolidin-3-yl)sulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrrolidin-1-yl]ethenone; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridine-2-carboxamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrrolidine-1-carboxamide; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4-ylsulfonyl)-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]furan-2-carboxamide; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(methylsulfonylmethylsulfonyl)-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-methylsulfonylpropylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2-furyl]-(3-hydroxyazetidin-1-yl)methanone; 3-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]-1,4-dihydro-1,2,4-triazol-5-one; Tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate;6-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridazin-3-amine; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine-2-carboxylate; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine-2-carboxylic acid; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine-2-carboxamide; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]azetidin-3-yl] methyl carbonate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-methoxy-3-methyl-azetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3S)-3-methoxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[dimethyl(oxo)-¿6-sulfanylidene]propenamide; [2-(Aminomethyl)-3-hydroxy-2-methyl-propyl] 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(3-methyloxetan-3-yl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(1-methylcyclopropyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-methoxy-2-methyl-propyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3R)-3-methoxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[[(2S)-oxetan-2-yl]methyl]propenamide; 2-[4-Chloro-5-[(3R,4R)-1-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3- yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine;N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]cyclopropanesulfonamide; [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-yl]urea; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(4H-1,2,4-triazol-3-yl)ethylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(3-methyloxetan-3-yl)methylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; Tert-butyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-4-piperidyl] methyl carbonate; [(3R)-1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- 1-piperidyl]sulfonyl]propanoyl]pyrrolidin-3-yl] methyl carbonate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[[(2S)-tetrahydrofuran-2-yl]methyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[[(2R)-tetrahydrofuran-2-yl]methyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[(3R)-tetrahydrofuran-3-yl]propenamide; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]piperidin-4-one; 1-(Azetidin-1-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-methylsulfonylazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[1-(hydroxymethyl)cyclobutyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[1-(hydroxymethyl)cyclopentyl]propenamide;3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(4-hydroxycyclohexyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(5-methyl-1,3,4-oxadiazol-2-yl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(5-fluoro-2-pyridyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-methylpyrazol-3-yl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-fluoroazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(6-oxa-1-azaspiro[3.3]heptan-1-yl)propan-1-one; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-4-piperidyl] acetate; 5-[[(3S,4S)-4-[4-Fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-amine; 5-[[(3R,4R)-4-[4-Fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-amine; N-(Azetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]propanamide; 2-[4-Chloro-5-[(3R,4R)-1-[[1-[(4-methoxyphenyl)methyl]triazol-4-yl]methylsulfonyl]- 3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4-ylmethylsulfonyl)-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-3-methoxy-pyridazine; 5-Fluoro-2-[4-fluoro-5-[(3S,4S)-3-methyl-1-methylsulfonyl-4-piperidyl]-1H-imidazol- 2-yl]pyridine;5-Fluoro-2-[4-fluoro-5-[(3R,4R)-3-methyl-1-methylsulfonyl-4-piperidyl]-1H- imidazol-2-yl]pyridine; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]acetamide; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylate; Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylate; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]methanesulfonamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylic acid; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylic acid; Methyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate; N-(1-Acetylazetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(1-methylsulfonylazetidin-3-yl)propenamide; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1,3,4-thiadiazol-2-yl]acetamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylic acid; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]propane-1,3-diol; Methyl 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetate; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1,3,4-thiadiazol-2-amine;N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-yl]azetidine-3-carboxamide; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetic acid; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxamide; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-hydroxy-1,1-dimethyl-ethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(3,3-difluorocyclobutyl)propenamide; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-3-methyl-azetidin-3-yl] acetate; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-3-methyl-azetidin-3-yl] methyl carbonate; and [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]azetidin-3-yl] ethyl carbonate; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I according to any one of claims 1 to 19, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. A compound of formula I according to any one of claims 1 to 19, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

22. A compound of formula I according to any one of claims 1 to 19, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.

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